Background: Mutations in the PMM2 gene cause phosphomannomutase 2 deficiency (PMM2; MIM# 212065), which manifests as a congenital disorder of glycosylation (PMM2-CDG). Mutant PMM2 leads to the reduced conversion of Man-6-P to Man-1-P, which results in low concentrations of guanosine 5'-diphospho-D-mannose, a nucleotide-activated sugar essential for the construction of protein oligosaccharide chains. To date the only therapeutic options are preventive and symptomatic.
Scope of review: This review covers the latest advances in the search for a treatment for PMM2-CDG.
Major conclusions: Treatments based on increasing Man-1-P levels have been proposed, along with the administration of different mannose derivates, employing enzyme inhibitors or repurposed drugs to increase the synthesis of GDP-Man. A single repurposed drug that might alleviate a severe neurological symptom associated with the disorder is now in clinical use. Proof of concept also exists regarding the use of pharmacological chaperones and/or proteostatic regulators to increase the concentration of hypomorphic PMM2 mutant proteins.
General significance: The ongoing challenges facing the discovery of drugs to treat this orphan disease are discussed.
Keywords: Congenital disorders of glycosylation; Mannose; PMM2-CDG; Pharmacological chaperones; Phosphomannomutase; Proteostasis regulators.
Copyright © 2020. Published by Elsevier B.V.