Impaired glucose-1,6-biphosphate production due to bi-allelic PGM2L1 mutations is associated with a neurodevelopmental disorder

Eva Morava, Ulrich A. Schatz, Pernille M. Torring, Mary Alice Abbott, Matthias Baumann, Charlotte Brasch-Andersen, Nathalie Chevalier, Ulrike Dunkhase-Heinl, Martin Fleger, Tobias B. Haack, Stephen Nelson, Sven Potelle, Silvia Radenkovic, Guido T. Bommer, Emile Van Schaftingen, Maria Veiga-da-Cunha*

*Corresponding author for this work

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We describe a genetic syndrome due to PGM2L1 deficiency. PGM2 and PGM2L1 make hexose-bisphosphates, like glucose-1,6-bisphosphate, which are indispensable cofactors for sugar phosphomutases. These enzymes form the hexose-1-phosphates crucial for NDP-sugars synthesis and ensuing glycosylation reactions. While PGM2 has a wide tissue distribution, PGM2L1 is highly expressed in the brain, accounting for the elevated concentrations of glucose-1,6-bisphosphate found there. Four individuals (three females and one male aged between 2 and 7.5 years) with bi-allelic inactivating mutations of PGM2L1 were identified by exome sequencing. All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris. Early obesity and seizures were present in three individuals. Analysis of the children's fibroblasts showed that glucose-1,6-bisphosphate and other sugar bisphosphates were markedly reduced but still present at concentrations able to stimulate phosphomutases maximally. Hence, the concentrations of NDP-sugars and glycosylation of the heavily glycosylated protein LAMP2 were normal. Consistent with this, serum transferrin was normally glycosylated in affected individuals. PGM2L1 deficiency does not appear to be a glycosylation defect, but the clinical features observed in this neurodevelopmental disorder point toward an important but still unknown role of glucose-1,6-bisphosphate or other sugar bisphosphates in brain metabolism.

Original languageEnglish
JournalAmerican Journal of Human Genetics
Issue number6
Pages (from-to)1151-1160
Publication statusPublished - 3. Jun 2021

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  • brain development
  • congenital disorders of glycosylation
  • glucose-1,6-bisphosphatase
  • glucose-1,6-bisphosphate synthase
  • IMP
  • phosphoglucomutase
  • PMM1


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