It’s All in the Genes
15-year study uncovers first known genetic cause for rare retinal disease
Phoebe Harkin | | Quick Read
Paul Bernstein has spent 15 years working with macular telangiectasia type 2 (MacTel) patients – a rare inherited retinal disease that causes gradual loss of central vision in people over the age of 40. Bernstein’s job, along with others at the Lowy Medical Research Institute, was singular – to identify as many familial cases of MacTel as possible to aid in gene discovery. More than 250 patients enrolled in the program – part of an LMRI network of more than 30 centers around the world. It was one of those cases – a father and son – which led him to a breakthrough: a connection between HSAN1, a very rare hereditary sensory neuropathy, and MacTel.
“When we examined additional HSAN1 patients, it soon became clear that nearly all of them also had MacTel,” explains Bernstein, a Val A. and Edith D. Green Presidential Professor of Ophthalmology and Visual Sciences at the Moran Eye Center, University of Utah School of Medicine. He explains that HSAN1 is caused by mutations in a gene called SPTLC1 that codes for an enzyme that helps convert the amino acid, serine, into sphingolipids and ceramides. “Mutations in SPTLC1 alter the enzyme’s properties and lead to accumulation of toxic dihydrodeoxyceramides,” says Bernstein. “Although mutations in SPTLC1 are a very rare cause of MacTel, many MacTel patients also have high levels of dihyrodeoxyceramides, presumably due to other mutations in these pathways.”
To better understand the connection, the team conducted comprehensive eye exams on a group of 10 HSAN1 patients unrelated to the original Utah family. They found 7 out of 10 patients had MacTel. The researchers went on to assess patients who were too young to exhibit clinical signs of the disease using fluorescence lifetime imaging ophthalmoscopy. They found that all of the asymptomatic HSAN1 patients exhibited the “MacTel signature” – a characteristic crescent or ring in the macula – in their FLIO images, suggesting that they are at high risk of developing MacTel in the future.
The findings raise an interesting question: how many other genes could be linked to MacTel? “Like RP or AMD, there could be many,” says Bernstein, “Genome-wide association studies (GWAS) suggest at least two or three more.” Understanding the novel disease pathways that underlie MacTel is crucial, as they will guide targeted interventions in future clinical trials – for instance, high-dose serine supplementation alleviates the neuropathy associated with HSAN1. It is only through testing that researchers will be able to know if similar interventions could help patients with MacTel. “The MacTel project is a prime example of a large-scale philanthropically-funded international collaboration that has advanced knowledge of an orphan retinal disease,” says Bernstein – and perhaps other retinal diseases too.
“15 years ago, MacTel was a poorly understood, untreatable, ‘sporadic’ macular disease that was often misdiagnosed,” he explains. “We now have excellent diagnostic techniques such as OCT, autofluorescence and FLIO, and evidence that it is actually a complex inherited condition with incomplete genetic penetrance and late onset.” And while there is currently no available cure, hope is on the horizon. A randomized, sham-controlled clinical trial is underway, assessing the viability of an implant of encapsulated cells that secrete the neuroprotective growth factor, CNTF. Results are positive from the Phase 2 trial and Phase 3 is still enrolling worldwide. Bernstein is hopeful the study will continue to improve our collective understanding of MacTel and HSAN1 in the future. Here’s hoping.
- L Marin et al., “Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy”, N Engl J Med, Sep 11 (2019). PMID: 31509666.