Common BBS1 variant may leave wider window to protect vision

People with Bardet-Biedl syndrome (BBS) caused by a mutation called p.(Met390Arg) in both copies of the BBS1 gene may develop vision symptoms later and reach major vision loss at older ages than people with other BBS1 mutation combinations, according to a new study.

Data indicate that patients with this particular mutation may be good candidates for future treatments, such as gene replacement therapy, that aim to restore BBS1 activity and preserve eyesight, the scientists noted.

“The [p.(Met390Arg) mutation] represents the most common disease-causing variant in patients with BBS1-associated [eye damage], and as shown in this study, these patients tend to have a broad window for treatment compared with patients affected with other BBS genes; therefore, they are good candidates for gene replacement therapy,” the researchers wrote.

BBS1 mutations can damage the retina

The study, “Genetic and Phenotypic Characterization of a Large Cohort of Patients with BBS1-Retinopathy,” was published in Ophthalmology Science.

BBS is a rare genetic condition caused by problems with cellular structures called cilia. It can result in a wide range of symptoms, including obesity and problems with vision.

Eye symptoms occur because photoreceptors, the eye cells that detect light, are highly specialized cilia-based structures. When cilia aren’t working correctly, the retina — the light-sensitive layer at the back of the eye — can become damaged.

Mutations in more than two dozen different genes have been linked to BBS, but mutations in both copies of the BBS1 gene account for a substantial portion of cases.

Here, a team led by scientists in the U.K. set out to detail symptoms, including eye problems, that typically occur in people with BBS1-related disease, and to identify potential associations between genotype (genetic profile) and phenotype (clinical manifestations).

To do so, the researchers retrospectively reviewed demographic, clinical, and eye imaging data from 48 people (52.1% female) with BBS1-related retinal damage, with or without other BBS symptoms. All had disease-causing mutations in both copies of the BBS1 gene and were followed at a single hospital in the U.K.

Vision symptoms often began in young adulthood

The mean age at symptom onset was 18.1 years, and the first symptoms were most frequently central vision loss (37.5%) and night blindness, or difficulty seeing in low lighting (35.4%).

Apart from vision loss, the most commonly reported BBS symptoms were obesity, which affected 71% of those with body mass index data, and polydactyly or extra fingers and/or toes, which affected about half of participants. More than one-third of participants (35%) had intellectual disability, and 18.8% had kidney problems.

Participants had a mean age of 28.7 years at their first visit at the researchers’ hospital. At that time, vision tests showed more than half (58.3%) of participants had no or mild problems with vision. Another 27.1% met criteria for moderate visual impairment, 4.2% had severe visual impairment, and the remaining 10.4% fulfilled the criteria for blindness.

Almost all of the participants (97.9%) had long-term follow-up data available, with a mean follow-up time of 10.6 years. As of the latest follow-up, half had vision loss severe enough to be classified as blindness. Meanwhile, 22.9% had moderate vision impairment and 4.2% had severe impairment, while only 20.8% had no or mild visual impairment.

Comprehensive eye tests showed that eye damage in BBS1-related retinal disease tends to follow a specific pattern, with the center of the retina generally being “the earliest and most affected,” the team wrote.

Seven BBS1 mutations were identified across participants. p.(Met390Arg), the most common disease-causing variant in BBS1-related retinal damage, was also the most frequently identified mutation, present in 85.4% of patients.

Common mutation tied to later major vision loss

The team then used statistical models to look at potential genotype-phenotype correlations, or links between a person’s genetic profile and disease features. They found that patients who had a specific mutation, called p.(Met390Arg), in both BBS1 gene copies developed symptoms later and reached major vision loss at older ages than those with other BBS1 mutation combinations.

Specifically, 50% of participants with other BBS1 mutation combinations reached a major visual acuity loss threshold by age 30, compared with age 53 for those with p.(Met390Arg) in both BBS1 gene copies.

These data indicate that patients with p.(Met390Arg) in both BBS1 gene copies might be especially good candidates for future treatments aimed at slowing vision loss, the researchers noted.

“Despite early involvement of the central retina … BBS1 appears to have a relatively wide window for therapeutic intervention, especially in patients harboring the [p.(Met390Arg) mutation in both gene copies],” the team wrote.

“Also, given that many [body-wide] features in most cases are noted since birth or early childhood, these patients can be diagnosed early,” the researchers concluded. “Natural history studies [following patients over time] are needed to further determine clinical outcomes.”