Genetic and Clinical Heterogeneity in Thirteen New Cases with Aceruloplasminemia. Atypical Anemia as a Clue for an Early Diagnosis

Author(s):Show less -

Vila Cuenca, Marc ^[1] ; Marchi, Giacomo ^{[2, 3]} ; Barque, Anna ^[1] ; Esteban-Jurado, Clara ^[1] ; Marchetto, Alessandro ^[4] ; Giorgetti, Alejandro ^[4] ; Chelban, Viorica ^{[5, 6, 7]} ; Houlden, Henry ^{[5, 6, 8]} ; Wood, Nicholas W. ^{[5, 8]} ; Piubelli, Chiara ^[9] ; Borges, Marina Dorigatti ^[10] ; de Albuquerque, Dulcineia Martins ^[10] ; Fertrin, Kleber Yotsumoto ^{[10, 11]} ; Jove-Buxeda, Ester ^[12] ; Sanchez-Delgado, Jordi ^{[13, 14]} ; Baena-Diez, Neus ^[15] ; Burnyte, Birute ^[16] ; Utkus, Algirdas ^[16] ; Busti, Fabiana ^{[2, 3]} ; Kaubrys, Gintaras ^[17] ; Suku, Eda ^[4] ; Kowalczyk, Kamil ^[18] ; Karaszewski, Bartosz ^[18] ; Porter, John B. ^[19] ; Pollard, Sally ^[20] ; Eleftheriou, Perla ^[19] ; Bignell, Patricia ^[21] ; Girelli, Domenico ^{[2, 3]} ; Sanchez, Mayka ^{[22, 23, 24]}

Affiliation:Show less -

^[1] Josep Carreras Leukaemia Res Inst IJC, Iron Metab Regulat & Dis Grp, Campus Can Ruti, Barcelona 08916 - Spain

^[2] Azienda Osped Univ Integrata Verona, EuroBloodNet Referral Ctr Iron Disorders, I-37134 Verona - Italy

^[3] Azienda Osped Univ Integrata Verona, Grp Interdisciplinare Malattie Ferro, Internal Med Unit, I-37134 Verona - Italy

^[4] Univ Verona, Dept Biotechnol, I-37134 Verona - Italy

^[5] Natl Hosp Neurol & Neurosurg, London WC1N 3BG - England

^[6] UCL, Inst Neurol, Dept Neuromuscular Dis, London WC1N 3BG - England

^[7] Inst Emergency Med, Dept Neurol & Neurosurg, Toma Ciorba 1, MD-2052 Kishinev - Moldova

^[8] Natl Hosp Neurol & Neurosurg, Neurogenet Lab, London WC1N 3BG - England

^[9] Osped Sacro Cuore Don Calabria, Ctr Trop Dis, I-37024 Negrar, VR - Italy

^[10] Univ Estadual Campinas, Hematol & Hemotherapy Ctr Hemoctr Campinas, UNICAMP, BR-13083878 Campinas - Brazil

^[11] Univ Washington, Dept Med, Div Hematol, Seattle, WA 98195 - USA

^[12] Univ Autonoma Barcelona, Internal Med Dept, Parc Tauli Hosp Univ, Inst Invest & Innovacio Parc Tauli I3PT, Sabadell 08208 - Spain

^[13] Univ Autonoma Barcelona, Digest Dis Dept, Hepatol Unit, Inst Invest & Innovacio Parc Tauli I3PT, Parc Taul, Sabadell 08208 - Spain

^[14] Inst Salud Carlos III, Ctr Invest Biomed & Red Enfermedades Hepat & Dige, Madrid 28029 - Spain

^[15] Univ Autonoma Barcelona, Genet Dept, Parc Tauli Hosp Univ, Inst Invest & Innovacio Parc Tauli I3PT, Sabadell 08208 - Spain

^[16] Vilnius Univ, Fac Med, Inst Biomed Sci, Dept Human & Med Genet, LT-08661 Vilnius - Lithuania

^[17] Vilnius Univ, Fac Med, Inst Clin Med, Clin Neurol & Neurosurg, LT-08661 Vilnius - Lithuania

^[18] Med Univ Gdansk, Dept Adult Neurol, PL-80210 Gdansk - Poland

^[19] Univ Coll London NHS Fdn Trust, Haematol Dept, Canc Serv, Joint Red Cell Unit, 250 Euston Road, London NW1 2PG - England

^[20] Bradford Royal Infirm, Duckworthlane, Bradford BD9 6RJ, W Yorkshire - England

^[21] Oxford Univ Hosp NHS Fdn Trust, Churchill Hosp, Oxford Reg Genet Lab, Oxford OX3 7LE - England

^[22] Univ Int Catalunya UIC, Fac Med & Hlth Sci, Dept Basic Sci, Iron Metab Regulat & Dis Grp, Barcelona 08017 - Spain

^[23] Inst Invest Germans Trias & Pujol IGTP, Program Program Predict & Personalized Med Canc P, Campus Can Ruti, Barcelona 08916 - Spain

^[24] BloodGenet SL, Barcelona 08950 - Spain

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 21, n. 7 APR 2020.
• Web of Science Citations: 0

Abstract

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. (AU)

• FAPESP's process: 16/08072-9 - Characterization of molecular changes in patients with aceruloplasminemia
• Grantee: Marina Dorigatti Borges
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 14/00984-3 - Red blood cell disorders: pathophysiology and new therapeutic approaches
• Grantee: Fernando Ferreira Costa
• Support Opportunities: Research Projects - Thematic Grants