Background Pompe disease (PD) is a metabolic myopathy caused by α-glucosidase (GAA) deficiency and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the milder intermediate and late-onset forms. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), the only treatment available for PD, intriguingly shows variable efficacy in different PD patients. To investigate the mechanisms underlying the variable response to ERT, we studied cell morphology of PD fibroblasts, the distribution and trafficking of the cation-independent mannose-6-phosphate receptor (CI-MPR) that mediates rhGAA uptake, and rhGAA uptake itself.
Results We observed abnormalities of cell morphology in PD cells. Electron microscopy analysis showed accumulation of multivesicular bodies and expansion of the Golgi apparatus, and immunolocalization and western blot analysis of LC3 showed activation of autophagy. Immunofluorescence analysis showed abnormal intracellular distribution of CI-MPR in PD fibroblasts, increased co-localization with LC3 and reduced availability of the receptor at the plasma membrane. The recycling of CI-MPR from the plasma membrane to the trans-Golgi network was also impaired. All these abnormalities were more prominent in severe and intermediate PD fibroblasts, correlating with disease severity. In severe and intermediate PD cells rhGAA uptake and processing were less efficient and correction of GAA activity was reduced.
Conclusion These results indicate a role for disrupted CI-MPR trafficking in the variable response to ERT in PD and have implications for ERT efficacy and optimization of treatment protocols.
Background: MetabERN is one of the 24 European Reference Networks created according to the European Union directive 2011/24/EU on patient's rights in cross border healthcare. MetabERN associates 69 centres in 18 countries, which provide care for patients with Hereditary Metabolic Diseases, and have the mission to reinforce research and provide training for health professionals in this field. MetabERN performed a survey in December 2017 with the aim to produce an overview documenting research activities and potentials within the network. As the centres are multidisciplinary, separated questionnaires were sent to the clinical, university and laboratory teams. Answers were received from 52 out of the 69 centres of the network, covering 16 countries. A descriptive analysis of the information collected is presented. Results: The answers indicate a marked interest of the respondents for research, who expressed high motivation and commitment, and estimated that the conditions to do research in their institution were mostly satisfactory. They are active in research, which according to several indicators, is competitive and satisfies standards of excellence, as well as the education programs offered in the respondent's universities. Research in the centres is primarily performed in genetics, pathophysiology, and epidemiology, and focuses on issues related to diagnosis. Few respondents declared having activity in human and social sciences, including research on patient's quality of life, patient's awareness, or methods for social support. Infrastructures offering services for medical research were rarely known and used by respondents, including national and international biobanking platforms. In contrast, respondents often participate to patient registries, even beyond their specific field of interest. Conclusions: Taken as a whole, these results provide an encouraging picture of the research capacities and activities in the MetabERN network, which, with respect to the number and representativeness of the investigated centres, gives a comprehensive picture of research on Hereditary Metabolic Diseases in Europe, as well as the priorities for future actions. Marginal activity in human and social sciences points out the limited multidisciplinary constitution of the responding teams with possible consequences on their current capability to participate to patient's empowerment programs and efficiently collaborate with patient's advocacy groups.
In: Heard , J-M , Bellettato , C , van Lingen , C , Scarpa , M , Debray , F-G , Nassogne , M-C C , van Coster , R , de Meirleir , L , Eyskens , F , Morava , E , Baric , I , Kozich , V , Lund , A M , Germain , D , Belmatoug , N , Guffon , N , Labrune , P , Gouya , L , de Lonlay , P , Schiff , M , Dobbelaere , D , Chabrol , B , Das , A M , Spiekerkoetter , U , Rutsch , F , Ploeckinger , U , Mohnike , K , Hahn , A , Kölker , S , Ullrich , K , Balogh , I , Bembi , B , Donati , M A , Gasperini , S , Parenti , G , Salviati , A , Vici , C-D , di Rocco , M , Cefalo , G , Burlina , A , Ceccarini , G , Federico , A , van der Ploeg , A , Rubio-Gozalbo , M-E , van Spronsen , F , Visser , G , Bosch , A , Tangeraas , T , Sanderberg , S , Kieć-Wilk , B , Gaspar , A-M S M , Martins , E , Silva , E-M F R , de Abreu Freire Diogo Matos , L-M , Azevedo , O , Tansek , M-Z , Couce-Pico , M-L , Cazorla , A G , Azuara , L A-E , del Toro-Riera , M , Lajic , S , Darin , N , Deegan , P , Vijaym , S , Chronopoulou , E , Jones , S , Chakrapani , A & Hiwot , T 2019 , ' Research activity and capability in the European reference network MetabERN ' , Orphanet Journal of Rare Diseases , vol. 14 , no. 1 , 119 . https://doi.org/10.1186/s13023-019-1091-8
Background: MetabERN is one of the 24 European Reference Networks created according to the European Union directive 2011/24/EU on patient's rights in cross border healthcare. MetabERN associates 69 centres in 18 countries, which provide care for patients with Hereditary Metabolic Diseases, and have the mission to reinforce research and provide training for health professionals in this field. MetabERN performed a survey in December 2017 with the aim to produce an overview documenting research activities and potentials within the network. As the centres are multidisciplinary, separated questionnaires were sent to the clinical, university and laboratory teams. Answers were received from 52 out of the 69 centres of the network, covering 16 countries. A descriptive analysis of the information collected is presented. Results: The answers indicate a marked interest of the respondents for research, who expressed high motivation and commitment, and estimated that the conditions to do research in their institution were mostly satisfactory. They are active in research, which according to several indicators, is competitive and satisfies standards of excellence, as well as the education programs offered in the respondent's universities. Research in the centres is primarily performed in genetics, pathophysiology, and epidemiology, and focuses on issues related to diagnosis. Few respondents declared having activity in human and social sciences, including research on patient's quality of life, patient's awareness, or methods for social support. Infrastructures offering services for medical research were rarely known and used by respondents, including national and international biobanking platforms. In contrast, respondents often participate to patient registries, even beyond their specific field of interest. Conclusions: Taken as a whole, these results provide an encouraging picture of the research capacities and activities in the MetabERN network, which, with respect to the number and representativeness of the investigated centres, gives a comprehensive picture of research on Hereditary Metabolic Diseases in Europe, as well as the priorities for future actions. Marginal activity in human and social sciences points out the limited multidisciplinary constitution of the responding teams with possible consequences on their current capability to participate to patient's empowerment programs and efficiently collaborate with patient's advocacy groups.