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A defect in serine metabolism was found to be behind a rare macular disease, according to researchers reporting a new connection between central and peripheral neuropathies.

Genetic mutations in SPTLC1 and SPTLC2, known to cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), were also tied to macular telangiectasia type 2 from exome sequencing, according to a report by Martin Friedlander, MD, PhD, of The Lowy Medical Research Institute in La Jolla, California, and colleagues.

"HSAN1-associated variants in these genes lead to pathologic accumulation of deoxysphinganine; our data show that these mutations also cause macular telangiectasia type 2," the researchers wrote in the .

Most patients with macular telangiectasia type 2 in the study did not have variants in SPTLC1 or SPTLC2, but they did have 20.6% lower serine levels and 84.2% higher deoxysphingolipid levels compared with unaffected controls, the authors reported.

"In addition to finding that altered amino acid and sphingolipid metabolism were the basis of the photoreceptor loss in patients with macular telangiectasia type 2, we have expanded the definition of diseases caused by variants in SPTLC1 or SPTLC2 and have shown a link between abnormal systemic serine metabolism and tissue-specific disease," the researchers concluded.

"Abnormal serine metabolism, leading to increased levels of deoxysphingolipids, may represent a broader 'serineopathy' class of diseases that includes both retinal and peripheral neuropathies, and so it might be expected that patients with macular telangiectasia type 2 would also be at risk for peripheral neuropathies," the team explained.

Macular telangiectasia type 2 is known to have a complex inheritance pattern and has previously been associated with abnormal serine metabolism. SPTLC1 or SPTLC2 each encode a subunit of serine palmitoyltransferase (SPT), which is the rate-limiting enzyme in sphingolipid synthesis.

It's unknown why serine is so systemically low in patients with macular telangiectasia type 2.

"Given that serine is central to numerous metabolic pathways, the genetic regulators are probably diverse," Friedlander and colleagues proposed. "The multiple means of regulating serine and deoxysphingolipid levels may reflect the genetic heterogeneity observed in macular telangiectasia type 2. Variations in environmental factors, such as diet, could also explain the variable penetrance of macular telangiectasia type 2 in families."

Experiments in mice suggested that a serine-free diet led to more retinal deoxysphingolipids and worse vision. With human stem cell-derived retinal organoids, it was found that deoxy-dihydroceramide in particular was especially toxic to human photoreceptors, Friedlander's group showed.

"Further work is needed to understand the mechanism of retinal toxicity and the potential involvement of other sphingolipid metabolites," the investigators said.

For now, they cautioned against prescribing serine or fenofibrate to patients with macular telangiectasia type 2.

"This is a very interesting study with a backing of some nice science. The difficulty may be in how to apply it," commented Rick Spaide, MD, of Vitreous Retina Macula Consultants of New York and NYU Langone in New York City.

He noted the Warburg effect, whereby photoreceptors tend to use glycolytic metabolism even if there are higher levels of oxygen. Serine supports the one-carbon cycle, which is involved in energy production in cells, especially with glycolysis.

"While it may seem logical to give MacTel 2 patients something to feed into the one-carbon metabolism, there is a potential to cause unexpected side effects," Spaide told 木瓜直播. "The other class of cells that also show the Warburg effect are tumor cells. Systemic augmentation of one-carbon metabolism has the potential to enhance, and maybe induce, tumor growth."

"Perhaps it may be possible to use encapsulated cell therapy, now used in a study to deliver ciliary neurotrophic factor ... in a similar way to locally release higher levels of serine into the vitreous cavity to favorably affect deoxysphingolipid levels without an increased level of risk for systemic cancer," he suggested.

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