Phosphomannomutase 2-Congenital Disorder of Glycosylation (PMM2-CDG): Exploring the Role of N-Glycosylation on the Endocrine Axes

Giulia Del Medico¹Lorenzo Ferri²Elena Procopio³Giosuè Annibalini⁴Elena Barbieri^4,5Rita Barone^6,7Renzo Guerrini^2,8Amelia Morrone^2,8Stefano Stagi^10,9*

• ¹Health Sciences Department, University of Florence, Florence, Italy
• ²Department of Neuroscience and Medical Genetics, Meyer Children’s Hospital IRCCS, Florence, Italy
• ³Metabolic and Muscular Unit, Meyer Children’s Hospital IRCCS, Florence, Italy
• ⁴Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy
• ⁵IIM, Interuniversity Institute of Myology, Perugia, Italy
• ⁶Child Neurology and Psychiatry Unit, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
• ⁷Research Unit of Rare Diseases and Neurodevelopmental Disorders, Oasi Research Institute-IRCCS, Troina, Italy
• ⁸Department of NEUROFARBA: Neurosciences, Psychology, Pharmacology and Child Health, University of Florence, Florence, Italy
• ⁹Health Sciences Department, University of Florence, Florence, Italy;, Florence, Tuscany, Italy
• ¹⁰Auxoendocrinology Unit, Meyer Children’s Hospital IRCCS, Florence, Tuscany, Italy

Congenital disorders of glycosylation (CDG) are a heterogeneous group of inborn errors of metabolism caused by impaired protein glycosylation. Among these, PMM2-CDG, caused by defective phosphomannomutase 2 activity and affecting protein N-glycosylation, is the most prevalent. As glycoproteins are involved in almost every physiological process, the clinical manifestations in PMM2-CDG are diverse and multisystemic. In the endocrine system, glycoproteins are present in every axis, acting as hormones, prohormones, receptors, enzymes, and transport proteins. Hypoglycosylation can alter hormonal function on multiple levels. As a result, endocrinopathies are frequently part of the clinical spectrum of PMM2-CDG, particularly hypergonadotrophic hypogonadism and pubertal abnormalities in female patients. Symptoms of endocrine involvement, especially hyperinsulinemic hypoglycemia and failure to thrive during infancy, can be the presenting sign of the disease. The clinical spectrum of PMM2-CDG endocrinopathy is variable; for example, thyroid involvement can range from isolated transitory hyperthyrotropinemia to clinical hypothyroidism. Some endocrine abnormalities, such as adrenal insufficiency, are uncommon and probably underdiagnosed in PMM2-CDG. The new insights into the role of N-glycosylation on the endocrine system over the past twenty years have deepened our understanding of this complex disorder and should enable us to improve and personalize the clinical management of these patients.