Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature

Schiff, Manuel; Roda, Célina; Monin, Marie‐Lorraine; Arion, A.; Barth, Magali; Bednarek, Nathalie; Bidet, Maud; Bloch, Catherine; Boddaert, Nathalie; Borgel, Delphine; Brassier, Anaïs; Brice, Alexis; Bruneel, Arnaud; Buissonnière, Roger; Chabrol, B.; Chevalier, Marie-Chantal; Cormier‐Daire, Valérie; Barace, Claire de; Maistre, Emmanuel de; Saint‐Martin, Anne de; Dorison, Nathalie; Drouin‐Garraud, Valérie; Dupré, Thierry; Échenne, B.; Edery, Patrick; Feillet, François; I, Fontan; Francannet, Christine; Labarthe, François; Gitiaux, Cyril; Héron, Delphine; Hully, Marie; Lamoureux, Sylvie; Martin‐Coignard, Dominique; Mignot, Cyril; Morin, Gilles; Pascreau, Tiffany; Pincemaille, O; Polak, Michel; Roubertie, Agathe; Thauvin‐Robinet, Christel; Toutain, Annick; Viot, Géraldine; Vuillaumier‐Barrot, Sandrine; Seta, Nathalie; Lonlay, Pascale de

doi:10.1136/jmedgenet-2017-104903

Cited by 98 publications

(119 citation statements)

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“…Given that FIX, FXI, AT, PC, and PS are primarily affected in CDG, we chose to assay these coagulation factors. Indeed, we found that CDG syndrome affected the activity of clotting factors and plasma inhibitors.…”

Section: Resultsmentioning

confidence: 99%

“…The most frequent CDG is phosphomannomutase deficiency ( PMM2 ‐CDG) . The clinical symptoms of PMM2 ‐CDG may include failure to thrive, developmental delay, cerebellar ataxia, strabismus, skeletal findings, and cardiac or renal involvement . Coagulation factors, most of which are glycoproteins, are also frequently affected in CDG.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, patients with CDG may have a coagulation pattern that does not correspond to hepatocellular failure, factor consumption, or vitamin K deficiency. Indeed, low levels of both clotting factors (FIX and FXI) and coagulation inhibitors (especially AT, PC and protein S [PS]) are usually reported in the literature . Primary hemostasis might also be affected in patients with CDG; there is evidence of thrombocytopenia related to SLC35A1‐CDG (a form affecting a specific sialic acid transporter ) or the enhancement of platelet aggregation in PMM2‐CDGeven though the platelet N‐glycoproteins appear to be normal .…”

Section: Introductionmentioning

confidence: 99%

“…In childhood, PMM2 ‐CDG is marked by acute neurologic impairments mimicking stroke; these are commonly referred to as stroke‐like episodes. The episodes occur mainly during periods of fever or after head trauma, and are often revealed by confusional state, focal neurological deficit with mono‐ or hemiparesis, and sometimes, epileptic seizures . The hemostatic system's role in the pathophysiology of stroke‐like episodes has not yet been characterized.…”

Section: Introductionmentioning

confidence: 99%

“…During the first 72 hours of a stroke‐like episode, magnetic resonance imaging may reveal vasogenic edema that is not restricted to arterial territories; in contrast, ischemic occlusion is rarely observed . Stroke‐like episodes may affect up to 50% of patients with PMM2 ‐CDG . Thrombosis and hemorrhages are also reported in CDG, but are less frequent than stroke‐like episodes .…”

Section: Introductionmentioning

confidence: 99%

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Elevated thrombin generation in patients with congenital disorder of glycosylation and combined coagulation factor deficiencies

Pascreau

Morena‐Barrio

Lasne

et al. 2019

Journal of Thrombosis and Haemostasis

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Background Congenital disorders of glycosylation are rare inherited diseases affecting many different proteins. The lack of glycosylation notably affects the hemostatic system and leads to deficiencies of both procoagulant and anticoagulant factors. Objective To assess the hemostatic balance in patients with multiple coagulation disorders by using a thrombin generation assay. Method We performed conventional coagulation assays and a thrombin generation assay on samples from patients with congenital disorder of glycosylation. The thrombin generation assay was performed before and after activation of the protein C system by the addition of soluble thrombomodulin. Results A total of 35 patients were included: 71% and 57% had low antithrombin and factor XI levels, respectively. Protein C and protein S levels were abnormally low in 29% and 26% of the patients, respectively, whereas only 11% displayed low factor IX levels. Under baseline conditions, the thrombin generation assay revealed a significantly higher endogenous thrombin potential and thrombin peak in patients, relative to controls. After spiking with thrombomodulin, we observed impaired involvement of the protein C system. Hence, 54% of patients displayed a hypercoagulant phenotype in vitro. All the patients with a history of stroke‐like episodes or thrombosis displayed this hypercoagulant phenotype. Conclusion A thrombin generation assay revealed a hypercoagulant in vitro phenotype under baseline condition; this was accentuated by impaired involvement of the protein C system. This procoagulant phenotype may thus reflect the risk of severe vascular complications. Further research will have to determine whether the thrombin generation assay is predictive of vascular events.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Elevated thrombin generation in patients with congenital disorder of glycosylation and combined coagulation factor deficiencies

Pascreau

Morena‐Barrio

Lasne

et al. 2019

Journal of Thrombosis and Haemostasis

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Genotypes and estimated prevalence of phosphomannomutase 2 deficiency in Turkey differ significantly from those in Europe

Yıldız

Arslan²,

Çelik

et al. 2020

American J of Med Genetics Pt A

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Phosphomannomutase 2 deficiency (PMM2‐CDG) is an autosomal recessive congenital disorder of glycosylation, characterized by multisystem phenotypes, mostly including neurological involvement. In Turkey, due to high rates of consanguinity, many patients with autosomal recessive disorders have homozygous variants and these diseases are more common, compared to Europe. However, published reports of PMM2‐CDG from Turkey are scarce. Here, we describe clinical and molecular characteristics of PMM2‐CDG patients diagnosed in three centers in Turkey, using data obtained retrospectively from hospital records. We also analyzed an in‐house exome database of 1,313 individuals for PMM2 variants and estimated allele, carrier and disease frequencies, using the Hardy–Weinberg law. Eleven patients were identified from 10 families, displaying similar characteristics to previous publications, with the exception of the first report of epilepsia partialis continua and increased prevalence of sensorineural hearing loss. p.Val231Met was the most common variant, and was homozygous in four patients. This novel genotype results in a neurological phenotype with subclinical visceral involvement. Exome database analysis showed an estimated prevalence of 1:286,726 for PMM2‐CDG, which is much lower than expected (1:20,000 in Europe) because of the lack of predominance of the common European p.Asp141His allele, associated with a severe phenotype (allele frequency of 1:2,622 compared to 1:252 in gnomAD). These data suggest that prevalence, phenotypes and genotypes of PMM2‐CDG in Turkey differ significantly from those in Europe: Milder phenotypes may be more common, but the disease itself rarer, requiring a higher clinical suspicion for diagnosis. The association of sensorineural hearing loss with PMM2‐CDG warrants further study.

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PMM2‐CDG and nephrotic syndrome: A case report

Banderali

Salvatici

Rovelli

et al. 2022

Clinical Case Reports

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PMM2-CDG is the most frequent CDG with more than 900 reported patients. It is a multisystem disease with variable phenotype. 1 Renal involvement is described in only 6% affected patients 2 with only a few describing nephrotic syndrome (NS). [3][4][5][6] | CASEWe report the case of a now aged 13-year-old girl who manifested with hypotonia, alternating strabismus and hypokinesia during her first months of life. First words and walking with support were at 24 months; thus, development was delayed. Metabolic (without serum transferrin IEF) and genetic investigations were normal (Table 1). Brain MRI showed incomplete myelination, cardiac US an atrial septal defect and auditory evoked potentials a maturation delay.At 2 years, she was admitted for lethargy. CT scan and cerebral MRI angiography showed venous sinus thrombosis with widespread damage of hypothalamus, thalamus, and basal ganglia with cerebellar atrophy. She subsequently developed a predominantly left quadriplegia with ataxia, intentional tremor, and seizures partially responding to treatment. She has no relevant family history.Until 3 years old, she was frequently admitted for recurrent episodes of both upper and lower airway infections. There was hypertransaminasemia (AST-ALT: 564-571 U/L) but no clotting abnormalities.At 4 years, she presented a status epilepticus and was admitted to our department. Pneumonia and NS (urine P/C ratio: 3.6 mg/mg, n.v. <0.2 mg/mg) were diagnosed, with oliguria, edema, hypertension, and hypoalbuminemia (2.4 g/L; n.v.30-50). Steroids were started (prednisone 60 mg/m 2 /day for 6 weeks, then 40 mg/m 2 /day for other 6 weeks) with progressive clinical remission (P/C ratio 0.1 mg/mg after 10 weeks of treatment with normal

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Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature

Abstract: PMM2-CDG clinical phenotype is heterogeneous in terms of clinical course, with no clear division between neurological and visceral presentations.

Cited by 98 publications

References 48 publications

Elevated thrombin generation in patients with congenital disorder of glycosylation and combined coagulation factor deficiencies

Elevated thrombin generation in patients with congenital disorder of glycosylation and combined coagulation factor deficiencies

Genotypes and estimated prevalence of phosphomannomutase 2 deficiency in Turkey differ significantly from those in Europe

PMM2‐CDG and nephrotic syndrome: A case report

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