CLINICAL AND GENETIC ASPECTS IN CONGENITAL DISORDERS OF GLYCOSYLATION (CDG)

ASTEGGIANO, CARLA; PAPAZOGLY M.; SULDRUP N.; DODELSON DE KREMER R.

Santiago de Chile

Congreso; X Congreso Latinoamericano de Errores Innatos del Metabolismo y Pezquisa Neonatal; 2015

SLEIMPN

Introduction: Congenital Disorders of Glycosylation (CDG) are human genetic diseases due to defects in the attachment of glycans to proteins, lipids and proteoglycans in the lumen of the endoplasmic reticulum (ER) and their elaboration in the Golgi apparatus. More than 110 affected genes have been described as N- or O-glycosylation disorders, encompassing CDG defects of nucleotide-sugar biosynthesis or transporters, glycosyltransferases, vesicular transport, as well as in lipid and glycosyl-phosphatidylinositol anchor glycosylation. The clinical features range from a severe multisystem to mild phenotype. They can affect nearly all organs and systems, but it is often associated with neurological impairments. Serum transferrin (Tf) is a key glycoprotein for the study of N-glycosylation diseases. Objective: To increase the detection of inherited glycosylation disorders in Latin American patients. Methodology: To study N-glycosilation disorders, serum transferrin (Tf) was analyzed by Isoelectric Focusing (IEF), High Performance Liquid Chromatography (HPLC), Capillary Electrophoresis (CE) and Mass Spectrometry (MS). Sanger sequencing and Whole Exome Sequence (WES), were carried out in gDNA to detect the affected gene. Results: A multisystem clinical phenotype was observed in five CDG-I (cytosolic or ER defects) and in one CDG-II (Golgi defects) patients. We detected three PMM2-CDG patients and two ALG2-CDG siblings by exome sequencing and confirmed by Sanger sequencing. We also identified COL6A2 mutations in a patient with CDG-II Tf pattern, with autosomal recessive myosclerosis myopathy, rather than a CDG disease. One CDG-IIx patient requires further analysis to detect the gene alteration. Conclusion: PMM2-CDG, the most frequent CDG, leads to the loss of phosphomannomutase 2 activity and presented clinical features highly variable (from a multisystem stage to a severe neurological presentation). ALG2-CDG, a rare form of CDG, was reported only in one patient deficient in alpha 1,3 mannosyltransferase presenting refractory epilepsy, maturation and mental disability, severe hypotonia, facial dysmorphia, weak tendon reflexes and hypsarrhythmia. Six from seven Argentinean CDG-x patients carried mutations in genes that alter glycosylation pathway. We highlight a broad screening of clinical features to suspect CDG in patients with inherited disorders and to develop Next Generation Sequence methods to discover new genes involved in CDG. Supported by CONICET/FONCYT/UCC/Sanford-Burnham Research Institute.