A new missense mutation in two ALG2-CDG Argentinean siblings

PAPAZOGLU MAGALÍ; NG BOBBY; PEREYRA MARCELA; AMOROSI CYNTIA; DODELSON DE KREMER RAQUEL; FREEZE HUDSON; ASTEGGIANO CARLA

Congreso; Annual Symposium of the Society for the Study of Inborn Errors of Metabolism.; 2016

Background: The disruption of glycan synthesis frequently results in a multisystemic disease with neurological involvement. Congenital Disorders of Glycosylation (CDG) are a group of human genetic diseases that involve different defects in the synthesis or remodeling of glycoconjugates. Multistep assembly of N-linked glycans by glycosyltransferases starts in the ER membrane with the 14-step synthesis of a lipid-linked oligosaccharide. ALG2 encodes for a mannosyltransferase that transfers 2 mannose residue from GDP-Mannose to Man1GlcNAc2-PP-dolichol at the cytosolic side of ER. ALG2-CDG [MIM-607906] is a rare form of CDG affecting N-glycoprotein biosynthesis. To date, a single patient has been described, presenting with bilateral iris colobomas, unilateral cataract, infantile spasms, severe developmental delay and abnormal coagulation factors [Thiel et al 2003]. Case Study: Multisystem clinical manifestations were observed in two siblings born from non-consanguineous parents, at diagnose (8 and 10 years-old), both patients presented refractory epilepsy, maturation and intellectual disability, facial dysmorphia, weak tendon reflexes and spasms in flexion. Images (NMR) showed frontotemporal atrophy, fundus appeared normal, and the electropherogram indicated hypsarrhythmia. Methods: A complex algorithm was done ranging from serum transferrin glycosylation status to exome sequencing to arrive at the likely diagnosis. Results: A CDG-I pattern was detected by three independent methods; IEF, CE and LCMS. Exome sequencing detected a homozygous missense mutation (c.752G˃T; p.R251H) in exon 2 of ALG2. Only maternal DNA was available for testing and it was determined she was a carrier for this mutation. Discussion: We have detected two new ALG2-CDG patients carrying a new mutation in this gene associated with CDG. We believe it is extremely important to contribute to the advance in the knowledge and diagnosis of CDG in Latin American patients.