Thrombotic complications in patients with PMM2-CDG

25.06.2013 10:00

Thrombotic complications in patients with PMM2-CDG

M. Linssen a,1, M. Mohamed a,1, R.A. Wevers b, D.J. Lefeber c, E. Morava a,d,

a Department of Pediatrics, Radboud University Nijmegen Medical Centre, Netherlands

b Laboratory of Genetic, Endocrine and Metabolic Disease, Radboud University Nijmegen Medical Centre, Netherlands

c Department of Neurology, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, Netherlands

d Hayward Genetics Center and Department of Pediatrics, Tulane University Medical School, New Orleans, LA, USA

a r t i c l e  i n f o  a b s t r a c t

Article history:

Received 7 February 2013

Accepted 8 February 2013

Available online 16 February 2013







Coagulation factors

Many proteins regulating coagulation, including factor IX, factor XI, Antithrombin-III, Protein C and Protein S are deficient or decreased in activity in congenital disorders of glycosylation (CDG). Because of the imbalance of coagulation and anticoagulation factors, some patients develop acute vascular events, such as thrombosis. Identifying patients with increased risk for thrombotic events could prevent serious complications and even mortality. We performed a systematic review on patients diagnosed with the most common CDG form; PMM2-CDG, reported between 1990 and 2012 in medical literature. We also evaluated our PMM2-CDG patient-cohort of 15 patients. In total, based on the availability of comprehensive clinical descriptions, 100 patients were included in the study. Patients with and without thrombotic events were compared based on the alterations of the following glycosylated coagulation and anticoagulation factors: Antithrombin-III, Protein C, Protein S, factors IX and XI. We also assessed the global hemostasis, family history and provoking events. In the group of 100 PMM2-CDG patients 14 had suffered a venous or arterial thrombotic event. Low activity of several anticoagulation factors correlated with thrombotic events. Relatively high factor IX and XI activities were not associated with thrombosis. Prolonged PT and aPTT did not seem to protect against thrombosis in patients. Surgical procedures were frequently associated with thrombotic events.

Based on the association of thrombosis and surgery in PMM2-CDG we advise to avoid elective surgical procedures in PMM2-CDG patients. Easily preventable risk factors like immobility should be treated with regular physiotherapy. We suggest a yearly follow-up for Antithrombin-III and Protein C levels and parent education for early thrombotic signs in CDG.

© 2013 Elsevier Inc. All rights reserved.

1. Introduction

Congenital disorders of glycosylation (CDG) are a growing group of inborn errors of metabolism of protein and lipid glycosylation with more than 50 different subtypes described since its discovery in 1980 [1]. This diverse group of disorders is divided into different biochemical subgroups based on the involvement of the N-linked, O-linked, combined (N- and O-linked) and lipid glycosylation pathways. The most common form of CDG; PMM2-CDG (previously CDG Ia), affects N-linked glycosylation, and occurs due to phosphomannomutase deficiency [1]. Even within the same subtype of CDG the clinical presentation is very heterogeneous. Symptoms including dysmorphic features, gastrointestinal, endocrine and central nervous systems involvement mostly present within a few months [2]. Some of the CDG patients develop acute vascular events, such as thrombosis or bleeding [3]. Proteins regulating the coagulation are often deficient in CDG syndrome [4]. Factor VIII, factor XI, Antithrombin-III (AT-III), Protein C and Protein S are most frequently abnormal, however factors II, V, VII, IX and X can also be decreased in some of the patients [5]. Recent studies demonstrate an imbalance of anticoagulation and procoagulation factors, disorganizing normal coagulation [2]. How this mechanism exactly works in children with CDG is yet to be discovered. Due to unexpected vascular complications some of the children affected by CDG might not get an optimal treatment, leading to serious complications, irreversible damage or even death [6,7]. In order to facilitate early diagnosis and prevention of thrombosis in future patients we retrospectively evaluated all the reported PMM2-CDG cases and assessed the occurrence of specific risk factors for thrombotic events.

2. Material and methods

We performed a retrospective, systematic review on all clinical trials and case reports reported between 1990 and 2012, including a total of 175 patients with PMM2-CDG. PMM2-CDG (CDG Ia) patients Molecular Genetics and Metabolism 109 (2013) 107111 Abbreviations: aPTT, activated thromboplastin time; AT-III, Antithrombin-III; CDG, congenital disorders of glycosylation; PT, prothrombin time; TIEF, transferrin isoelectric focusing.

The authors are all in agreement with the publication.

Corresponding author at:Hayward Genetics Center, Tulane UniversityMedical School, 1430 Tulane Ave, New Orleans, LA, 70112, USA.

E-mail address: (E. Morava).

1 Equal contribution.

1096-7192/$ see front matter © 2013 Elsevier Inc. All rights reserved.

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