PB0314 - Identification of Congenital Disorders of Glycosylation among Patients with Antithrombin Deficiency: Enhancing Diagnosis and its Therapeutic Implications.

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Co-Author(s)

ML

María Llamas-López, PhD-Student

Bioinformatician
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
CB

Carlos Bravo-Pérez

PhD MD
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
AM

Antonia Miñano

Tech
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
EW

Ewa Wypasek

MD
The John Paul II Hospital
Krakov, Malopolskie, Poland
MG

Mar Gutierrez-Albariño

Medical doctor
Servicio de Hematología, Hospital la Paz
Madrid, Madrid, Spain
EG

Eduardo García-Pérez

Hematologist
Servicio de Hematología, Hospital la Paz
Madrid, Madrid, Spain
BS

Blai Signes

Medical doctor
Servicio de Hematología, Complejo Hospitalario de Navarra
Pamplona, Navarra, Spain
Belén de la Morena-Barrio, PhD

Post-doc
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
Pedro Garrido-Rodríguez

PhD student
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
JP

Javier Pagán

Researcher and Medical Doctor
Servicio de Medicina Interna Hospital General Universitario Morales Messeguer.
Murcia, Murcia, Spain
TH

Trinidad Hernández

Researcher
Department of Biochemistry and Molecular Biology (B) and Immunology, Universidad de Murcia, IMIB-Pascual Parrilla
Murcia, Murcia, Spain
Irene Martínez Martínez

Researcher
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
VV

Vicente Vicente

Senior Researcher
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
AU

Anetta Undas

Professor
Department of Thromboembolic Disorders, Institute of Cardiology, Jagiellonian University Medical College
Kraków, Malopolskie, Poland
ML

María Luisa Lozano

Hematologist
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain
Javier Corral

Professor
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain

Presenting Author(s)

María Eugenia de la Morena-Barrio, PhD

PhD
Servicio de Hematología, Hospital General Universitario Morales Messeguer, Centro Regional de Hemodonación, Universidad de Murcia, Universidad de Murcia, IMIB-Pascual Parrilla, CIBERER-ISCIII
Murcia, Murcia, Spain

Background: Antithrombin deficiency (ATD) is a primary congenital thrombophilia caused by decreased levels of this key anticoagulant glycoprotein often stemming from SERPINC1 genetic defects. However, approximately 25% of cases lack SERPINC1 defects. Notably, patients with congenital disorders of glycosylation (CDG), a rare and severe multi-system disorder resulting from inefficient N-glycosylation, co-presented with ATD.

Aims: To identify and characterize CDGs by analyzing patients with ATD.

Methods: A total of 409 unrelated patients with ATD were recruited. SERPINC1 was evaluated through sequencing and MLPA. Hypoglycosylation of antithrombin, FXI, α1-antitrypsin, and transferrin was evaluated by western blot and/or HPLC and validated by PNGaseF. Exome or sequencing of 74 genes involved in N-glycosylation was performed.

Results: SERPINC1 defects were identified in 324 cases. Increased hypoglycosylated forms of antithrombin and other proteins were observed in 33 out of 85 patients without SERPINC1 defects (38.8%). Among these, six featured biallelic pathogenic variants affecting PMM2, MPI, ALG12, ALG13, or GALT. These patients exhibited severe ATD and high levels of hypoglycosylated transferrin, with minor or no psychomotor delay. Dietary interventions, such as mannose overload in MPI-CDG and galactose removal in GALT-CDG, improved antithrombin values, allowing for anticoagulation withdrawal and resolution of other clinical signs (Fig.1A&B). One patient carried bialellic likely-pathogenic variants in HK3, a gene not yet involved in CDG. Additionally, 19 of 85 cases with one pathogenic CDG-variant and mild-moderate alcohol intake showed restored antithrombin values upon cessation of alcohol intake, reducing hypoglycosylation (Fig.1C).

Conclusion(s): In one of the largest cohorts of ATD, we demonstrated that CDGs underlie 8% of this disorder (38.8% of cases without SERPINC1 defects). Classical CDGs with atypical clinical manifestations may be underdiagnosed. Furthermore, dietary treatments could enhance antithrombin levels and clinical management. Finally, we demonstrated the synergistic effects of alcohol intake coupled with a pathogenic variant in a glycosylation gene on ATD and hypoglycosylation phenotype. PI21/00174(ISCIII&UE);21886/PI/22(Fundación Séneca).