2e3b83211a8962c05b1817f9cdd1ca72 ijms-21-02374.pdf b71ce87bd8ca9e0b5ae67088d94e259322e2459b ijms-21-02374.pdf c11639e39e71ce0bc33dbbf663c1efa14d0076d56c91ce74ec6ff0d7e881d255 ijms-21-02374.pdf Title: Genetic and Clinical Heterogeneity in Thirteen New Cases with Aceruloplasminemia. Atypical Anemia as a Clue for an Early Diagnosis Subject: 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. Keywords: aceruloplasminemia; ceruloplasmin; iron metabolism; neurodegenerative disease; anemia; ferritin Author: Marc Vila Cuenca, Giacomo Marchi, Anna Barqué, Clara Esteban-Jurado, Alessandro Marchetto, Alejandro Giorgetti, Viorica Chelban, Henry Houlden, Nicholas W Wood, Chiara Piubelli, Marina Dorigatti Borges, Dulcinéia Martins de Albuquerque, Kleber Yotsumoto Fertrin, Ester Jové-Buxeda, Jordi Sanchez-Delgado, Neus Baena-Díez, Birute Burnyte, Algirdas Utkus, Fabiana Busti, Gintaras Kaubrys, Eda Suku, Kamil Kowalczyk, Bartosz Karaszewski, John B. Porter, Sally Pollard, Perla Eleftheriou, Patricia Bignell, Domenico Girelli and Mayka Sanchez Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Mon Mar 30 12:26:50 2020 CEST ModDate: Mon Mar 30 12:26:50 2020 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 14 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1239597 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- EHXQFO+URWPalladioL-Ital Type 1 Custom yes yes no 71 0 UZJLQV+URWPalladioL-Bold Type 1 Custom yes yes no 72 0 QTLELQ+Pxbsy Type 1 Builtin yes yes no 73 0 YSPQJI+VnURWPalladioL-Bold Type 1 Custom yes yes no 74 0 NSGKLR+URWPalladioL-Roma Type 1 Custom yes yes no 75 0 ISIQYD+VnURWPalladioL Type 1 Custom yes yes no 76 0 SYXPPI+Rpxr Type 1 Builtin yes yes no 77 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 82 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