• Laura C Tegtmeyer, Stephan Rust, Monique van Scherpenzeel, Bobby G Ng, Marie-Estelle Losfeld, Sharita Timal, Kimiyo Raymond, Ping He, Mie Ichikawa, Joris Veltman, Karin Huijben, Yoon S Shin, Vandana Sharma, Maciej Adamowicz, Martin Lammens, Janine Reunert, Anika Witten, Esther Schrapers, Gert Matthijs, Jaak Jaeken, Daisy Rymen, Tanya Stojkovic, Pascal Laforêt, François Petit, Olivier Aumaître, Elzbieta Czarnowska, Monique Piraud, Teodor Podskarbi, Charles A Stanley, Reuben Matalon, Patricie Burda, Soraya Seyyedi, Volker Debus, Piotr Socha, Jolanta Sykut-Cegielska, Francjan van Spronsen, Linda de Meirleir, Pietro Vajro, Terry DeClue, Can Ficicioglu, Yoshinao Wada, Ron A Wevers, Dieter Vanderschaeghe, Nico Callewaert, Ralph Fingerhut, Emile van Schaftingen, Hudson H Freeze, Eva Morava, Dirk J Lefeber, and Thorsten Marquardt.
• The authors' affiliations are listed in the Appendix.
• N. Engl. J. Med.. 2014 Feb 6;370(6):533-42.

BackgroundCongenital disorders of glycosylation are genetic syndromes that result in impaired glycoprotein production. We evaluated patients who had a novel recessive disorder of glycosylation, with a range of clinical manifestations that included hepatopathy, bifid uvula, malignant hyperthermia, hypogonadotropic hypogonadism, growth retardation, hypoglycemia, myopathy, dilated cardiomyopathy, and cardiac arrest.MethodsHomozygosity mapping followed by whole-exome sequencing was used to identify a mutation in the gene for phosphoglucomutase 1 (PGM1) in two siblings. Sequencing identified additional mutations in 15 other families. Phosphoglucomutase 1 enzyme activity was assayed on cell extracts. Analyses of glycosylation efficiency and quantitative studies of sugar metabolites were performed. Galactose supplementation in fibroblast cultures and dietary supplementation in the patients were studied to determine the effect on glycosylation.ResultsPhosphoglucomutase 1 enzyme activity was markedly diminished in all patients. Mass spectrometry of transferrin showed a loss of complete N-glycans and the presence of truncated glycans lacking galactose. Fibroblasts supplemented with galactose showed restoration of protein glycosylation and no evidence of glycogen accumulation. Dietary supplementation with galactose in six patients resulted in changes suggestive of clinical improvement. A new screening test showed good discrimination between patients and controls.ConclusionsPhosphoglucomutase 1 deficiency, previously identified as a glycogenosis, is also a congenital disorder of glycosylation. Supplementation with galactose leads to biochemical improvement in indexes of glycosylation in cells and patients, and supplementation with complex carbohydrates stabilizes blood glucose. A new screening test has been developed but has not yet been validated. (Funded by the Netherlands Organization for Scientific Research and others.).

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