Dataset Information

29 French adult patients with PMM2-congenital disorder of glycosylation: outcome of the classical pediatric phenotype and depiction of a late-onset phenotype.

ABSTRACT: PMM2-CDG (formerly known as CDG Ia) a deficiency in phosphomannomutase, is the most frequent congenital disorder of glycosylation. The phenotype encompasses a wide range of neurological and non-neurological manifestations comprising cerebellar atrophy and intellectual deficiency. The phenotype of the disorder is well characterized in children but the long term course of the disease is unknown and the phenotype of late onset forms has not been comprehensively described. We thus retrospectively collected the clinical, biological and radiological data of 29 French PMM2-CDG patients aged 15 years or more with a proven molecular diagnosis (16 females and 13 males). In addition, thirteen of these patients were reexamined at the time of the study to obtain detailed information. 27 of the 29 patients had a typical PMM2-CDG phenotype, with infantile hypotonia, strabismus, developmental delay followed by intellectual deficiency, epilepsy, retinitis pigmentosa and/or visceral manifestations. The main health problems for these patients as teenagers and in adulthood were primary ovarian insufficiency, growth retardation, coagulation anomalies and thrombotic events, skeletal deformities and osteopenia/osteoporosis, retinitis pigmentosa, as well as peripheral neuropathy. Three patients had never walked and three lost their ability to walk. The two remaining patients had a late-onset phenotype unreported to date. All patients (n = 29) had stable cerebellar atrophy. Our findings are in line with those of previous adult PMM2-CDG cohorts and points to the need for a multidisciplinary approach to the follow up of PMM2-CDG patients to prevent late complications. Additionally, our findings add weight to the view that PMM2-CDG may be diagnosed in teenage/adult patients with cerebellar atrophy, even in the absence of intellectual deficiency or non-neurological involvement.

SUBMITTER: Monin ML

PROVIDER: S-EPMC4266234 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

29 French adult patients with PMM2-congenital disorder of glycosylation: outcome of the classical pediatric phenotype and depiction of a late-onset phenotype.

Monin Marie-Lorraine ML Mignot Cyril C De Lonlay Pascale P Héron Bénédicte B Masurel Alice A Mathieu-Dramard Michèle M Lenaerts Catherine C Thauvin Christel C Gérard Marion M Roze Emmanuel E Jacquette Aurélia A Charles Perrine P de Baracé Claire C Drouin-Garraud Valérie V Khau Van Kien Philippe P Cormier-Daire Valérie V Mayer Michèle M Ogier Hélène H Brice Alexis A Seta Nathalie N Héron Delphine D

Orphanet journal of rare diseases 20141211

PMM2-CDG (formerly known as CDG Ia) a deficiency in phosphomannomutase, is the most frequent congenital disorder of glycosylation. The phenotype encompasses a wide range of neurological and non-neurological manifestations comprising cerebellar atrophy and intellectual deficiency. The phenotype of the disorder is well characterized in children but the long term course of the disease is unknown and the phenotype of late onset forms has not been comprehensively described. We thus retrospectively co ...[more]

PMID: 25497157

Similar Datasets

Project description:PMM2-CDG, formerly known as congenital disorder of glycosylation-Ia (CDG-Ia), is caused by mutations in the gene encoding phosphomannomutase 2 (PMM2). This disease is the most frequent form of inherited CDG-diseases affecting protein N-glycosylation in human. PMM2-CDG is a multisystemic disease with severe psychomotor and mental retardation. In order to study the pathophysiology of PMM2-CDG in a human cell culture model, we generated induced pluripotent stem cells (iPSCs) from fibroblasts of a PMM2-CDG-patient (PMM2-iPSCs). Expression of pluripotency factors andin vitrodifferentiation into cell types of the three germ layers was unaffected in the analyzed clone PMM2-iPSC-C3 compared with nondiseased human pluripotent stem cells (hPSCs), revealing no broader influence of the PMM2 mutation on pluripotency in cell culture. Analysis of gene expression by deep-sequencing did not show obvious differences in the transcriptome between PMM2-iPSC-C3 and nondiseased hPSCs. By multiplexed capillary gel electrophoresis coupled to laser induced fluorescence detection (xCGE-LIF) we could show that PMM2-iPSC-C3 exhibit the common hPSC N-glycosylation pattern with high-mannose-type N-glycans as the predominant species. However, phosphomannomutase activity of PMM2-iPSC-C3 was 27% compared with control hPSCs and lectin staining revealed an overall reduced protein glycosylation. In addition, quantitative assessment of N-glycosylation by xCGE-LIF showed an up to 40% reduction of high-mannose-type N-glycans in PMM2-iPSC-C3, which was in concordance to the observed reduction of the Glc3Man9GlcNAc2 lipid-linked oligosaccharide compared with control hPSCs. Thus we could model the PMM2-CDG disease phenotype of hypoglycosylation with patient derived iPSCsin vitro Knock-down ofPMM2by shRNA in PMM2-iPSC-C3 led to a residual activity of 5% and to a further reduction of the level of N-glycosylation. Taken together we have developed human stem cell-based cell culture models with stepwise reduced levels of N-glycosylation now enabling to study the role of N-glycosylation during early human development.

Project description:BackgroundCongenital disorders of glycosylation (CDG) are a growing group of rare genetic disorders. The most common CDG is phosphomannomutase 2 (PMM2)-CDG which often has a severe clinical presentation and life-limiting consequences. There are no approved therapies for this condition. Also, there are no validated disease-specific quality of life (QoL) scales to assess the heterogeneous clinical burden of PMM2-CDG which presents a challenge for the assessment of the disease severity and the impact of a certain treatment on the course of the disease.Aim and methodsThis study aimed to identify the most impactful clinical signs and symptoms of PMM2-CDG, and specific patient and observer reported outcome measures (PROMs and ObsROMs, respectively) that can adequately measure such impact on patients' QoL. The most burdensome signs and symptoms were identified through input from the CDG community using a survey targeting PMM2-CDG families and experts, followed by family interviews to understand the real burden of these symptoms in daily life. The list of signs and symptoms was then verified and refined by patient representatives and medical experts in the field. Finally, a literature search for PROMs and ObsROMs used in other rare or common diseases with similar signs and symptoms to those of PMM2-CDG was performed.ResultsTwenty-four signs/symptoms were identified as the most impactful throughout PMM2-CDG patients' lifetime. We found 239 articles that included tools to measure those community-selected PMM2-CDG symptoms. Among them, we identified 80 QoL scales that address those signs and symptoms and, subsequently, their psychometric quality was analysed. These scales could be applied directly to the PMM2-CDG population or adapted to create the first PMM2-CDG-specific QoL questionnaire.ConclusionIdentifying the impactful clinical manifestations of PMM2-CDG, along with the collection of PROMs/ObsROMs assessing QoL using a creative and community-centric methodology are the first step towards the development of a new, tailored, and specific PMM2-CDG QoL questionnaire. These findings can be used to fill a gap in PMM2-CDG clinical development. Importantly, this methodology is transferable to other CDG and rare diseases with multiple signs and symptoms.

Dataset Information

29 French adult patients with PMM2-congenital disorder of glycosylation: outcome of the classical pediatric phenotype and depiction of a late-onset phenotype.

Publications

29 French adult patients with PMM2-congenital disorder of glycosylation: outcome of the classical pediatric phenotype and depiction of a late-onset phenotype.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets