Genetic mutation led to development of severe childhood glaucoma: Study

New genetic mutation may be the source of severe cases of childhood glaucoma, a debilitating condition that runs in families and can cause blindness in children as young as three years old, according to a team of researchers.

Publication of Clinical Investigation, a journal, published the findings. The thrombospondin-1 (THBS1) gene was mutated in three ethnically and geographically varied families with a history of childhood glaucoma, according to cutting-edge genome-sequencing techniques. The scientists further verified their results in a mouse model that had the genetic mutation and manifested glaucoma symptoms due to a previously unidentified disease mechanism.

The new findings, published December 1 in the Journal of Clinical Investigation, could lead to improved screening for childhood glaucoma and more targeted treatments to prevent vision loss in children with the mutation, according to the study’s authors.

“This is a very exciting finding for families affected by childhood glaucoma,” said Janey L. Wiggs, MD, PhD, Associate Chief of Ophthalmology Clinical Research at Mass Eye and Ear and the Vice Chair for Ophthalmology Clinical Research and Paul Austin Chandler Professor of Ophthalmology at Harvard Medical School. “With this new knowledge, we can offer genetic testing to identify children in a family who may be at risk for the disease and start disease surveillance and conventional treatments earlier to preserve their vision. In the future, we would look to develop new therapies to target this genetic mutation.”

Leading cause of childhood blindness

Childhood, or congenital glaucoma is a rare but serious disease that presents in children as early as birth and as late as 3 years of age. Despite its rarity, childhood glaucoma is responsible for 5 percent of cases of child blindness worldwide.

Glaucoma causes irreversible damage to the eye’s optic nerve, often due to buildup of pressure inside the eye (intraocular pressure, or IOP). In adults, this damage can occur over time without symptoms, which is why the disease is often referred to as a “sneak thief of sight.”

Children and babies with childhood glaucoma, however, can be born with severe disease and vision loss or lose their vision later in childhood due to elevated IOP. This increase in pressure not only damages the optic nerve but can also affect other structures in a child’s eye like the cornea. Children with childhood glaucoma typically require surgeries as early as the first three to six months of life, followed by several more operations throughout their childhood.

With childhood glaucoma, there is typically a strong hereditary component often with multiple members of a family affected by the condition. According to Dr Wiggs, by better understanding the genes involved, genetic testing can give affected families peace of mind to learn whether their child might be at risk for developing the disease.

Uncovering the genetic underpinnings of disease

For decades, researchers have turned towards genetics to better understand the cause of glaucoma. When Dr Wiggs first began this line of research 30 years ago, scientists were only able to identify regions of the genome affected in glaucoma. Thanks to advances in genomic technology, researchers gained the ability to review the complete genetic makeup of individuals with and without glaucoma to determine which specific genetic mutations play a role in the disease. Research led by Dr Wiggs in 2021 used a dataset of more than 34,000 adults with glaucoma to identify 127 genes associated with the condition.

To better study the genetic mutations in childhood glaucoma, Dr Wiggs and her Mass Eye and Ear team first looked at exome sequences from an American family of European-Caucasian descent who had been part of an earlier research project and found a striking and novel variant in thrombospondin-1, a well-known protein in the body involved in a number of important biological processes, such as the formation of new vessels (angiogenesis) and tissues. This mutated gene was not found in people without childhood glaucoma, nor in large population genetic databases.

The amino acid altered by the mutation was evolutionarily conserved, indicating an important role in the protein function. This finding led Dr. Wiggs to connect with colleagues at Flinders University in Australia to see if they had any childhood glaucoma families with thrombospondin mutations. They surprisingly found two families with an alteration at the same amino acid: one of mixed European and Indian descent, and one Sudanese family originally from Africa.

“What was really striking about this finding is that these families all possessed this genetic variant, and it was not possible for them to be related because they were from such diverse backgrounds,” said Dr Wiggs. “That meant there was something really important about this mutation.”

To further test this hypothesis, the researchers collaborated with Robert J. D’Amato, MD, PhD, the Judah Folkman Chair in Surgery in the Vascular Biology Program at Boston Children’s Hospital, and a professor of Ophthalmology at Harvard Medical School. Dr. D’Amato’s team developed a mouse model with the THBS1 mutation and found that the mouse also had features of glaucoma.

“Thrombospondin-1 is well known as a potent inhibitor of blood vessel growth, or angiogenesis,” said Dr. D’Amato, who has studied angiogenesis for more than three decades. “I assumed at first that THBS1 mutations were disrupting blood vessel formation in the eye, but our animal models showed normal angiogenesis. We realized that there must be another mechanism.”

Specifically, D’Amato’s lab showed that the mutation caused abnormal thrombospondin proteins to accumulate in the intraocular drainage structures of the eye involved with regulating IOP, which in turn, led to a buildup of pressure that damaged the optic nerve and led to the loss of retinal ganglion cells, thereby causing vision loss.

This was the first time that researchers identified this kind of disease mechanism for causing childhood glaucoma.
“This work highlights the power of international collaborations,” said study co-author Owen M. Siggs MD, DPhil, associate professor at Flinders University and the Garvan Institute of Medical Research in Australia. “There’s such incredible genetic diversity across the globe, and comparing this information is becoming more and more critical for discoveries like this.”
Personalizing care for families with future study.

The new study has significant clinical implications, according to the researchers. While more work remains before comprehensive genetic testing can be offered, every gene that is found presents another opportunity to be able to identify causative mutations in these families through screening, according to the authors.

Therapeutically, understanding this gene mutation may enable early use of traditional medicines. For instance, if a child is born with this mutation, their eye care professional will be better able to alert the parents to the dangers and create a strategy for disease monitoring and care.

Finding this novel mechanism and gene that causes paediatric glaucoma may potentially result in the development of novel treatments that target the buildup of aberrant proteins. In addition, the researchers want to know if additional THBS1 mutations contribute to adult-onset diseases such primary open-angle glaucoma or less severe variations of the illness if the mutation is less severe.

In order to eventually create a highly thorough genetic profile for childhood glaucoma, researchers will also keep searching for novel genes linked to the disease.