Muscle Deficit Associated with Congenital Disorders of Glycosylation.

ASTEGGIANO CG

Cuidad de Mexico

Conferencia; 5th Latin American Congress of Glycobiology and 2nd. Meeting of the Glycoscience in Thematic Network; 2019

Sociedad Latinoamericana de Glicobiologia

In humans, rare diseases (EPOF) constitute an extensive and complex group of clinical entities that affect 7% of the world population [WHO 90 2012], with potentially 42 million affected individuals in Latin America. Within the large group of pathologies grouped as EPOF, the Congenital Disorders of Glycosylation (CDG) constitute a relevant group of more than 130 hereditary entities, caused by deficiencies in genes involved in the pathways of glycoconjugates, which affect the functional structure of glycoproteins, their intracellular transit and / or in the target of them. The clinical phenotype of CDG patients in general is complex, with multisystemic clinical manifestations depending on the affected cell process (Asteggiano CG et al, 2018). However, certain classes of CDG, constitute stereotyped clinical forms, with early onset muscle deficit, with or without involvement of the central nervous system. They are associated with alterations in genes that encode glycosyltransferases responsible for N-glycosylation of proteins involved in the activity of the neuromuscular plate or responsible for O-glycosylation of proteins located in the sarcolemma (Monies D. et al, 2014). The N-glycosylation of proteins is carried out through the transfer of a core glycan (RE) to asparagine residue of the nascent protein. Alterations in the genes ALG2, ALG14, DPAGT1 and GFPT1 (N-glycosylation) produce clinical manifestations associated with congenital myasthenic syndromes (CMS). O-glycosylation of proteins, involves the binding of glycans to serine, threonine or hydroxylysine (RE or Golgi) and there are seven different types of glycans according to the first sugar attached. The O-mannosylation of α-dystroglycan (sarcolemmal glycoprotein complex), is essential for structural function between the cytoskeleton and the matrix (Brancaccio, 2019). Alteration of O-glycosylation of α-DG is due to mutations in some of the 18 genes involved in this process (Manya & Endo, 2017). Among them we can mention the genes DPM1, DPM2, DMP3, FKTN, FKRP, LARGE, POMT1, POMT2 and POMGNT1, a group called dystroglycanopathies. Clinically they manifest as a form of muscular dystrophy associated with a varied spectrum of central nervous system involvement in the Walker Warburg (WWS), muscle-eye-brain (SEM) syndromes and Fukuyama congenital muscular dystrophy, among others. In Latin America the prevalence is unknown, in the European population they are 40 %, the most frequent forms of congenital muscular dystrophies. The differential diagnosis requires a multidisciplinary clinical evaluation, complementing biochemical, pathological and genetic-molecular studies (gene panels or massive sequencing). Diagnosis of these pathologies, allows us to provide adequate treatment guidelines and familiar genetic counseling, in addition to establishing relationships between genotypes and clinical phenotypes, sub-grouping potential beneficiaries of future pharmacological treatments.