Sjanie Huang, Eline G. P. van de Ven, Trisha Tee, Dirk J. Lefeber
Sialic acid (Sia) is essential for human physiology and health, as emphasized by the range of human diseases that is linked to abnormalities in the Sia pathway. Sias are typically found at the outermost part of glycoconjugates that are involved in several biological processes, including cell adhesion and signaling. Sia metabolism is key to the production of cytidine 5'-monophosphate-Sia, the building block for sialylation, and is targeted as a therapeutic strategy to ameliorate the effects of abnormal sialylation in disease. Interestingly, patients with different genetic defects in Sia metabolism show contrasting clinical symptoms affecting different tissues. For example, neurological symptoms are dominant in some congenital disorders of glycosylation, like patients with a deficiency in N-acetylneuraminate synthase, causing NANS-CDG, while the brain is unaffected in patients with a deficiency in UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase which results in isolated muscle symptoms. This suggests that more complex tissue-specific regulatory mechanisms may exist. In this review, we discuss the biosynthetic and genetic pathways in Sia metabolism with a specific focus on its role in brain, muscle, and platelets in health and genetic disease. Moreover, this review presents an overview of the clinical symptoms and genetic spectrum for each genetic disease. Overall, the molecular and biochemical profiles are not fully understood in these patients, and effective therapies are limited. Therefore, additional research should focus on unravelling metabolic mechanisms that could be targeted to develop novel therapeutic strategies.