Towards a new era for the identification and characterisation of inborn errors of glycosylation
Final Report Abstract
Congenital disorders of glycosylation (CDG) are a rapidly growing and heterogeneous group of rare, genetic diseases of metabolism. Patients with a deficiency in glycosylation present with an extremely variable and complex phenotype with developmental delay and multi-organ involvement, accompanied by neurologic symptoms and dysmorphic features. Within this collaborative project, we have combined ‘omics’ techniques to significantly expand the knowledge of the CDG diseases. Among other things, we identified a number of new patients suffering from ATP6V1A, ATP6V0A2, ALG9 and PMM2 CDG. New genetic variants as well as additional clinical symptoms were added to the scientific knowledge. In-depth analysis of ATP6V1A-CDG and ATP6V0A2-CDG defects in human and mouse material point to a disturbed vATPase assembly and activity at the Golgi compartment as well as abnormalities in other endocytic and degradative compartments. Furthermore, the 30 patients known to date who suffer from one of the fucosylation defects (SLC35C1-CDG, FCSK-CDG, FUT8-CDG, POFUT1-CDG and GFUS-CDG) were summarized. Since patients with these defects cannot usually be recognized in routine CDG diagnostics, our description of clinical similarities will help to identify new patients with fucosylation deficiency in the future. VPS13B, ATP9A and GOSR2 were added as new candidate genes for CDG deficiencies. We could further show that biallelic variants in MVK not only lead to mevalonic aciduria but to CDG as well. Furthermore, we were able to describe GFUS-CDG as a new glycosylation defect from the area of fucosylation, for which oral L-fucose supplementation represents a simple, safe and effective treatment option. Our OMICS investigation on the most common CDG defect, PMM2-CDG, demonstrated that a glycosylation deficiency has significant effects on several metabolites resulting in a general metabolic imbalance concerning amino acids, acylcarnitines, lipids, energy supply as well as lysosomal and peroxisomal breakdown. Since some of these abnormalities are directly related to each other, this opens up new possibilities for therapeutic approaches. Notably, based on these analyses, the reduction of biotinidase activity could also be identified as a probable key player for the development of a number of clinical symptoms known in CDG. A first corresponding study with the vitamin biotin indicates an improvement in cognitive abilities in patients. In contrast to all other therapeutic approaches, biotin is not limited to a specific CDG type and can be used for all N- glycosylation defects as well as for O-glycosylation (core-1 mucin type) and combined N- and O-glycosylation defects.
Publications
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Fatal outcome after heart surgery in PMM2-CDG due to a rare homozygous gene variant with double effects. Molecular Genetics and Metabolism Reports, 25, 100673.
Görlacher, Marlen; Panagiotou, Eleftheria; Himmelreich, Nastassja; Hüllen, Andreas; Beedgen, Lars; Dimitrov, Bianca; Geiger, Virginia; Zielonka, Matthias; Peters, Verena; Strahl, Sabine; Vázquez-Jiménez, Jaime; Kerst, Gunter & Thiel, Christian
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A spoonful of L‐fucose—an efficient therapy for GFUS‐CDG, a new glycosylation disorder. EMBO Molecular Medicine, 13(9).
Feichtinger, René G.; Hüllen, Andreas; Koller, Andreas; Kotzot, Dieter; Grote, Valerian; Rapp, Erdmann; Hofbauer, Peter; Brugger, Karin; Thiel, Christian; Mayr, Johannes A. & Wortmann, Saskia B.
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Biallelic truncating variants in ATP9A cause a novel neurodevelopmental disorder involving postnatal microcephaly and failure to thrive. Journal of Medical Genetics, 59(7), 662-668.
Vogt, Guido; Verheyen, Sarah; Schwartzmann, Sarina; Ehmke, Nadja; Potratz, Cornelia; Schwerin-Nagel, Anette; Plecko, Barbara; Holtgrewe, Manuel; Seelow, Dominik; Blatterer, Jasmin; Speicher, Michael R.; Kornak, Uwe; Horn, Denise; Mundlos, Stefan; Fischer-Zirnsak, Björn & Boschann, Felix
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Congenital disorders of glycosylation with defective fucosylation. Journal of Inherited Metabolic Disease, 44(6), 1441-1452.
Hüllen, Andreas; Falkenstein, Kristina; Weigel, Corina; Huidekoper, Hidde; Naumann‐Bartsch, Nora; Spenger, Johannes; Feichtinger, René G.; Schaefers, Jacqueline; Frenz, Stephanie; Kotlarz, Daniel; Momen, Tooba; Khoshnevisan, Razieh; Riedhammer, Korbinian M.; Santer, René; Herget, Theresia; Rennings, Alexander; Lefeber, Dirk J.; Mayr, Johannes A.; Thiel, Christian & Wortmann, Saskia B.
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Expanding the clinical and molecular spectrum of ATP6V1A related metabolic cutis laxa. Journal of Inherited Metabolic Disease, 44(4), 972-986.
Vogt, Guido; El Choubassi, Naji; Herczegfalvi, Ágnes; Kölbel, Heike; Lekaj, Anja; Schara, Ulrike; Holtgrewe, Manuel; Krause, Sabine; Horvath, Rita; Schuelke, Markus; Hübner, Christoph; Mundlos, Stefan; Roos, Andreas; Lochmüller, Hanns; Karcagi, Veronika; Kornak, Uwe & Fischer‐Zirnsak, Björn
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Missense variant c.1460 T > C (p.L487P) enhances protein degradation of ER mannosyltransferase ALG9 in two new ALG9-CDG patients presenting with West syndrome and review of the literature. Molecular Genetics and Metabolism, 136(4), 274-281.
Himmelreich, Nastassja; Dimitrov, Bianca; Zielonka, Matthias; Hüllen, Andreas; Hoffmann, Georg Friedrich; Juenger, Hendrik; Müller, Herbert; Lorenz, Imke; Busse, Birgit; Marschall, Christoph; Schlüter, Gregor & Thiel, Christian
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Complex metabolic disharmony in PMM2-CDG paves the way to new therapeutic approaches. Molecular Genetics and Metabolism, 139(3), 107610.
Himmelreich, Nastassja; Kikul, Frauke; Zdrazilova, Lucie; Honzik, Tomáš; Hecker, Andreas; Poschet, Gernot; Lüchtenborg, Christian; Brügger, Britta; Strahl, Sabine; Bürger, Friederike; Okun, Jürgen G.; Hansikova, Hana & Thiel, Christian
