2 January 2019

Dirk Lefeber and colleagues have discovered that the sugar sialic acid is important for good muscle and heart function. In a family with muscle problems, they discovered a mistake in a gene that prevents the breakdown of sialic acid.

It is the first time that the importance of the breakdown of sialic acid for humans has been investigated. The acquired knowledge offers new possibilities for treatment. In zebrafish, for example, they were able to treat the genetic disorder with a sugar diet.

Degradation of sugar

Our body has a metabolic pathway to break down sialic acid, but the role of that degradation was not yet known. Researchers from Canada and the Netherlands have now clarified this role. Pediatrician Clara van Karnebeek, now working in Amsterdam, discovered with her Canadian team a family with a hereditary fault in the N-acetylneuraminate pyruvate lyase (NPL) gene. NPL is necessary for the breakdown of sialic acid. The patients had an increased excretion of sialic acid in the urine and complained about muscle ache. Through a combination of new genetic techniques and better techniques for measuring sugars, the researchers were able to demonstrate that the gene NPL was the cause of the disease.

Important role

Sialic acid is a sugar molecule that is common in the human body. It is used as a building block to build sugar chains into proteins. In this way it plays an important role in, for example, brain development, the immune system and kidney function. Hereditary diseases in the construction of sialic acid therefore lead to neurological diseases and problems with infections or the kidneys. Sialic acid also plays a role in non-congenital diseases, such as various types of cancer.

Glycosylation disorders

Research in zebrafish showed that the NPL gene was needed for normal muscle function. The NPL is necessary for the production of another sugar, N-acetyl mannosamine, in short called ManNAc. And exactly this sugar was missing in the patients with this hereditary condition. Dirk Lefeber, professor in Glycosylation Disorders: "Remarkably, we found this effect only in the red blood cells of the patients, but not in other cell types. Apparently this specific process only works in certain organs, such as the muscle. "

Possible treatment

The new insight - that the absence of ManNAc can lead to muscle and heart problems - led to an experiment in zebrafish with the same genetic defect found in humans. The researchers saw that after the addition of ManNAc sugar, the symptoms in zebrafish disappeared. Whether a treatment with ManNAc in people works efficiently will now be further investigated.

Publication in JCI Insight: Sialic acid catabolism by N-acetylneuraminate pyruvate lyase is essential for muscle function

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