Metabolic Link to MacTel Confirmed

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An international research collaboration has discovered that a deficiency of the amino acid serine is associated with the accumulation of certain toxic lipids in the blood and ret­ina, causing photoreceptor apoptosis in macular telangiectasia (MacTel) type 2.¹

The new finding about this orphan disease points researchers toward a pos­sible molecular road map for slowing or preventing retinal degeneration in MacTel, said Martin Friedlander, MD, PhD, at Lowy Medical Research Insti­tute in La Jolla, California. “Through this highly collaborative project, we now have an understanding of macular telangiectasia. If you see a patient with MacTel, you should tell them that new research has revealed a cause of the disease and that we might have a treat­ment in the next few years,” said Dr. Friedlander, also at Scripps Research and Scripps Clinic in La Jolla.

COMPLEX INTERACTION. The researchers cautioned against prescribing fenofibrate or serine supplements to patients with MacTel type 2, “given the complex genetic etiology of the condition and the genetic diversity in the patient population.”

Building the case. In 2017, the Mac­Tel research group first reported on the suspected retinal role of serine,² which is used in many pathways in the body but was not previously known to affect macular health.

In the current study, the researchers confirmed the link, and they deter­mined that low serine levels lead to the same lipid-associated degenerative pro­cess that occurs in a rare genetic disease called hereditary sensory and autonom­ic neuropathy 1 (HSAN1).¹ Moreover, they identified the gene common to both MacTel and HSAN1, although this genetic variant is found in only a small number of MacTel patients, Dr. Friedlander said.

Tracking toxicity. Through a pain-staking combination of genetic analysis, metabolomics, animal studies, and in vitro tests in human retinal organoids grown from stem cells, the scientists de­termined that insufficient serine leads to the formation of toxic deoxysphin­golipids in the retina. These toxic molecules form instead of normal sphin­golipids when serine is lacking, Dr. Friedlander said.

When the researchers examined 13 HSAN1 patients who had not previously had ophthalmic testing, nine had un­diagnosed MacTel, and two more had early signs of the disease. Furthermore, blood tests in 125 MacTel patients showed levels of deoxysphingolipids 84.2% higher than those found in unaf­fected controls.

A new disease class? “In this case, a single biochemical mechanism causes disease in both the eye and the periph­eral nervous system,” Dr. Friedlander said. “We think this is an example of a new class of neurodegenerative disease that we are calling ‘serineopathies.’” He added that the finding may have appli­cation to more common metabolic and neurological disorders. For instance, he noted, elevated blood levels of deox­ysphingolipids have been reported in people with diabetic retinopathy.³

Patient management. The MacTel researchers found that cell damage was prevented if the scientists either supplemented with serine or used a drug that regulates lipid metabolism to block the toxic lipids from forming, Dr. Friedlander said. (For this study, they used fenofibrate.)

Already, some physicians are treat­ing HSAN1 patients with oral serine supplements, Dr. Friedlander said. But it is too early to recommend this for patients who have MacTel or are at genetic risk for it, he said. For now, he recommended that patients whose neu­ropathy has been diagnosed as HSAN1 be examined for signs of macular telan­giectasia.

—Linda Roach

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1 Ganter ML et al. N Engl J Med. 2019;381(15):1422-1433.

2 Scerri TS et al. Nat Genet. 2017;49(4):559-567.

3 Zuellig RA et al. Diabetes. 2014;63(4):1326-1329.

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Relevant financial disclosures—Dr. Friedlander: None.

For full disclosures and the disclosure key, see below.

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