Genetic and Clinical Heterogeneity in Thirteen New Cases with Aceruloplasminemia. Atypical Anemia as a Clue for an Early Diagnosis.
Por:
Vila Cuenca M, Marchi G, Barqué A, Esteban-Jurado C, Marchetto A, Giorgetti A, Chelban V, Houlden H, Wood NW, Piubelli C, Dorigatti Borges M, Martins de Albuquerque D, Yotsumoto Fertrin K, Jové-Buxeda E, Sanchez-Delgado J, Baena-Díez N, Burnyte B, Utkus A, Busti F, Kaubrys G, Suku E, Kowalczyk K, Karaszewski B, Porter JB, Pollard S, Eleftheriou P, Bignell P, Girelli D and Sanchez M
Publicada:
30 mar 2020
Ahead of Print:
30 mar 2020
Resumen:
Aceruloplasminemia is a rare autosomal recessive genetic disease characterized by mild microcytic anemia, diabetes, retinopathy, liver disease, and progressive neurological symptoms due to iron accumulation in pancreas, retina, liver, and brain. The disease is caused by mutations in the Ceruloplasmin (CP) gene that produce a strong reduction or absence of ceruloplasmin ferroxidase activity, leading to an impairment of iron metabolism. Most patients described so far are from Japan. Prompt diagnosis and therapy are crucial to prevent neurological complications since, once established, they are usually irreversible. Here, we describe the largest series of non-Japanese patients with aceruloplasminemia published so far, including 13 individuals from 11 families carrying 13 mutations in the CP gene (7 missense, 3 frameshifts, and 3 splicing mutations), 10 of which are novel. All missense mutations were studied by computational modeling. Clinical manifestations were heterogeneous, but anemia, often but not necessarily microcytic, was frequently the earliest one. This study confirms the clinical and genetic heterogeneity of aceruloplasminemia, a disease expected to be increasingly diagnosed in the Next-Generation Sequencing (NGS) era. Unexplained anemia with low transferrin saturation and high ferritin levels without inflammation should prompt the suspicion of aceruloplasminemia, which can be easily confirmed by low serum ceruloplasmin levels. Collaborative joint efforts are needed to better understand the pathophysiology of this potentially disabling disease.
Filiaciones:
Vila Cuenca M:
Iron Metabolism: Regulation and Diseases Group, Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, Badalona, 08916 Barcelona, Spain
Marchi G:
EuroBloodNet Referral Center for Iron Disorders and Gruppo Interdisciplinare Malattie del Ferro, Internal Medicine Unit, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy
Barqué A:
Iron Metabolism: Regulation and Diseases Group, Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, Badalona, 08916 Barcelona, Spain
Esteban-Jurado C:
Iron Metabolism: Regulation and Diseases Group, Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, Badalona, 08916 Barcelona, Spain
Marchetto A:
Department of Biotechnology, University of Verona, 37134 Verona, Italy
Giorgetti A:
Department of Biotechnology, University of Verona, 37134 Verona, Italy
Chelban V:
National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK
Department of Neuromuscular Diseases, Institute of Neurology, University College London, London WC1N 3BG, UK
Department of Neurology and Neurosurgery, Institute of Emergency Medicine, Toma Ciorba 1, Chisinau, MD-2052 Chisinau, Republic of Moldova
Houlden H:
National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK
Department of Neuromuscular Diseases, Institute of Neurology, University College London, London WC1N 3BG, UK
Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK
Wood NW:
National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK
Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK
Piubelli C:
Centre for Tropical Diseases, Ospedale Sacro Cuore - Don Calabria, 37024 Negrar (VR), Italy
Dorigatti Borges M:
Hematology and Hemotherapy Center-Hemocentro Campinas, University of Campinas-UNICAMP, Campinas 13083-878, Brazil
Martins de Albuquerque D:
Hematology and Hemotherapy Center-Hemocentro Campinas, University of Campinas-UNICAMP, Campinas 13083-878, Brazil
Yotsumoto Fertrin K:
Hematology and Hemotherapy Center-Hemocentro Campinas, University of Campinas-UNICAMP, Campinas 13083-878, Brazil
Division of Hematology, Department of Medicine, University of Washington, Seattle, WA 98195, USA
Jové-Buxeda E:
Internal Medicine Department, Parc Tauli Hospital Universitari, Institut d' Investigació i Innovació Parc Tauli I3PT, Universidad Autonoma de Barcelona, 08208 Sabadell, Spain
Sanchez-Delgado J:
Hepatology Unit, Digestive Diseases Department, Parc Tauli Hospital Universitari. Institut d' Investigació i Innovació Parc Tauli I3PT, Universidad Autonoma de Barcelona, 08208 Sabadell, Spain
Centro de Investigación Biomedica y en red Enfermedades hepáticas y digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
Baena-Díez N:
Genetic Department, Parc Tauli Hospital Universitari, Institut d' Investigació i Innovació Parc Tauli I3PT, Universidad Autonoma de Barcelona, 08208 Sabadell, Spain
Burnyte B:
Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-08661 Vilnius, Lithuania
Utkus A:
Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-08661 Vilnius, Lithuania
Busti F:
EuroBloodNet Referral Center for Iron Disorders and Gruppo Interdisciplinare Malattie del Ferro, Internal Medicine Unit, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy
Kaubrys G:
Clinic of Neurology and Neurosurgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 08661 Vilnius, Lithuania
Suku E:
Department of Biotechnology, University of Verona, 37134 Verona, Italy
Kowalczyk K:
Department of Adult Neurology, Medical University of Gdansk, 80-210 Gdansk, Poland
Karaszewski B:
Department of Adult Neurology, Medical University of Gdansk, 80-210 Gdansk, Poland
Porter JB:
Joint Red Cell Unit, Haematology Department, University College London NHS Foundation Trust, Cancer Services, 250 Euston Road, London NW1 2PG, UK
Pollard S:
Consultant Paediatrician, Bradford Royal Infirmary, Duckworthlane, Bradford BD9 6RJ, UK
Eleftheriou P:
Joint Red Cell Unit, Haematology Department, University College London NHS Foundation Trust, Cancer Services, 250 Euston Road, London NW1 2PG, UK
Bignell P:
Oxford Regional Genetics Laboratory, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford OX3 7LE, UK
Girelli D:
EuroBloodNet Referral Center for Iron Disorders and Gruppo Interdisciplinare Malattie del Ferro, Internal Medicine Unit, Azienda Ospedaliera Universitaria Integrata di Verona, 37134 Verona, Italy
:
Iron Metabolism: Regulation and Diseases Group, Department of Basic Sciences, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya (UIC)
Sant Cugat del Valles, 08017 Barcelona, Spain
Program of Program of Predictive and Personalized Medicine of Cancer (PMPPC), Institut d 'Investigació Germans Trias i Pujol (IGTP), Campus Can Ruti, Badalona, 08916 Barcelona, Spain
BloodGenetics S.L., Esplugues de Llobregat, 08950 Barcelona, Spain
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