Phenotypic heterogeneity in seven Italian cases of aceruloplasminemia

Sara Pelucchi, Raffaella Mariani, Giulia Ravasi, I Pelloni, M Marano, L Tremolizzo, M Alessio, Alberto Piperno

Research output: Contribution to journalArticle

Abstract

Introduction: Aceruloplasminemia is an ultra-rare hereditary disorder characterized by iron-restricted microcytic anemia and tissue iron overload associated with diabetes, retinal and progressive neurological degeneration. We describe genotypes and phenotypes at diagnosis, and disease evolution of seven Italian patients. Methods: Anagraphical, biochemical, genetic, clinical and instrumental data were collected at diagnosis and during a long-term follow-up. Mutations, ferroxidase activity and Western Blot analysis of ceruloplasmin were performed according to standard protocols. Results: Three mutations were already described (p.Phe217Ser, deletions of exon 11 and 12), p.Ile991Thr is a very rare variant, p.Cys338Ser and IVS6+1G > A were novel mutations. In silico analyses suggested they were highly likely or likely to be damaging. At diagnosis, 100% had microcytosis, 86% had mild-moderate anemia, low serum iron and high serum ferritin. Four (57%) had type 1 diabetes or glucose intolerance, 3/7 had neurological manifestations, and only one had early diabetic retinopathy. All but one underwent iron chelation therapy requiring temporary discontinuation because of anemia worsening. At the end of follow-up, three patients aggravated and 2 developed neurological symptoms; only two patients were free of neurological manifestations and showed mild or absent brain iron. Conclusion: Aceruloplasminemia phenotypes ranged from classical characterized by progressive neurologic derangement to milder in which signs of systemic iron overload prevailed over brain iron accumulation. Within this large heterogeneity, microcytosis with or without anemia, low serum iron and high serum ferritin were the early hallmarks of the disease. Therapeutic approaches other than iron chelation should be explored to reduce morbidity and improve life expectancy. © 2018 Elsevier Ltd
Original languageEnglish
Pages (from-to)36-42
Number of pages7
JournalParkinsonism and Related Disorders
Volume51
DOIs
Publication statusPublished - 2018

Fingerprint

Iron
Anemia
Ceruloplasmin
Iron Overload
Ferritins
Neurologic Manifestations
Serum
Mutation
Chelation Therapy
Phenotype
Glucose Intolerance
Brain
Diabetic Retinopathy
Life Expectancy
Familial apoceruloplasmin deficiency
Type 1 Diabetes Mellitus
Computer Simulation
Nervous System
Molecular Biology
Exons

Cite this

Pelucchi, S., Mariani, R., Ravasi, G., Pelloni, I., Marano, M., Tremolizzo, L., ... Piperno, A. (2018). Phenotypic heterogeneity in seven Italian cases of aceruloplasminemia. Parkinsonism and Related Disorders, 51, 36-42. https://doi.org/10.1016/j.parkreldis.2018.02.036

Phenotypic heterogeneity in seven Italian cases of aceruloplasminemia. / Pelucchi, Sara; Mariani, Raffaella; Ravasi, Giulia; Pelloni, I; Marano, M; Tremolizzo, L; Alessio, M; Piperno, Alberto.

In: Parkinsonism and Related Disorders, Vol. 51, 2018, p. 36-42.

Research output: Contribution to journalArticle

Pelucchi, S, Mariani, R, Ravasi, G, Pelloni, I, Marano, M, Tremolizzo, L, Alessio, M & Piperno, A 2018, 'Phenotypic heterogeneity in seven Italian cases of aceruloplasminemia', Parkinsonism and Related Disorders, vol. 51, pp. 36-42. https://doi.org/10.1016/j.parkreldis.2018.02.036
Pelucchi, Sara ; Mariani, Raffaella ; Ravasi, Giulia ; Pelloni, I ; Marano, M ; Tremolizzo, L ; Alessio, M ; Piperno, Alberto. / Phenotypic heterogeneity in seven Italian cases of aceruloplasminemia. In: Parkinsonism and Related Disorders. 2018 ; Vol. 51. pp. 36-42.
@article{f0d8f00cc167416fb198a7560967d9a8,
title = "Phenotypic heterogeneity in seven Italian cases of aceruloplasminemia",
abstract = "Introduction: Aceruloplasminemia is an ultra-rare hereditary disorder characterized by iron-restricted microcytic anemia and tissue iron overload associated with diabetes, retinal and progressive neurological degeneration. We describe genotypes and phenotypes at diagnosis, and disease evolution of seven Italian patients. Methods: Anagraphical, biochemical, genetic, clinical and instrumental data were collected at diagnosis and during a long-term follow-up. Mutations, ferroxidase activity and Western Blot analysis of ceruloplasmin were performed according to standard protocols. Results: Three mutations were already described (p.Phe217Ser, deletions of exon 11 and 12), p.Ile991Thr is a very rare variant, p.Cys338Ser and IVS6+1G > A were novel mutations. In silico analyses suggested they were highly likely or likely to be damaging. At diagnosis, 100{\%} had microcytosis, 86{\%} had mild-moderate anemia, low serum iron and high serum ferritin. Four (57{\%}) had type 1 diabetes or glucose intolerance, 3/7 had neurological manifestations, and only one had early diabetic retinopathy. All but one underwent iron chelation therapy requiring temporary discontinuation because of anemia worsening. At the end of follow-up, three patients aggravated and 2 developed neurological symptoms; only two patients were free of neurological manifestations and showed mild or absent brain iron. Conclusion: Aceruloplasminemia phenotypes ranged from classical characterized by progressive neurologic derangement to milder in which signs of systemic iron overload prevailed over brain iron accumulation. Within this large heterogeneity, microcytosis with or without anemia, low serum iron and high serum ferritin were the early hallmarks of the disease. Therapeutic approaches other than iron chelation should be explored to reduce morbidity and improve life expectancy. {\circledC} 2018 Elsevier Ltd",
author = "Sara Pelucchi and Raffaella Mariani and Giulia Ravasi and I Pelloni and M Marano and L Tremolizzo and M Alessio and Alberto Piperno",
year = "2018",
doi = "10.1016/j.parkreldis.2018.02.036",
language = "English",
volume = "51",
pages = "36--42",
journal = "Parkinsonism and Related Disorders",
issn = "1353-8020",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - Phenotypic heterogeneity in seven Italian cases of aceruloplasminemia

AU - Pelucchi, Sara

AU - Mariani, Raffaella

AU - Ravasi, Giulia

AU - Pelloni, I

AU - Marano, M

AU - Tremolizzo, L

AU - Alessio, M

AU - Piperno, Alberto

PY - 2018

Y1 - 2018

N2 - Introduction: Aceruloplasminemia is an ultra-rare hereditary disorder characterized by iron-restricted microcytic anemia and tissue iron overload associated with diabetes, retinal and progressive neurological degeneration. We describe genotypes and phenotypes at diagnosis, and disease evolution of seven Italian patients. Methods: Anagraphical, biochemical, genetic, clinical and instrumental data were collected at diagnosis and during a long-term follow-up. Mutations, ferroxidase activity and Western Blot analysis of ceruloplasmin were performed according to standard protocols. Results: Three mutations were already described (p.Phe217Ser, deletions of exon 11 and 12), p.Ile991Thr is a very rare variant, p.Cys338Ser and IVS6+1G > A were novel mutations. In silico analyses suggested they were highly likely or likely to be damaging. At diagnosis, 100% had microcytosis, 86% had mild-moderate anemia, low serum iron and high serum ferritin. Four (57%) had type 1 diabetes or glucose intolerance, 3/7 had neurological manifestations, and only one had early diabetic retinopathy. All but one underwent iron chelation therapy requiring temporary discontinuation because of anemia worsening. At the end of follow-up, three patients aggravated and 2 developed neurological symptoms; only two patients were free of neurological manifestations and showed mild or absent brain iron. Conclusion: Aceruloplasminemia phenotypes ranged from classical characterized by progressive neurologic derangement to milder in which signs of systemic iron overload prevailed over brain iron accumulation. Within this large heterogeneity, microcytosis with or without anemia, low serum iron and high serum ferritin were the early hallmarks of the disease. Therapeutic approaches other than iron chelation should be explored to reduce morbidity and improve life expectancy. © 2018 Elsevier Ltd

AB - Introduction: Aceruloplasminemia is an ultra-rare hereditary disorder characterized by iron-restricted microcytic anemia and tissue iron overload associated with diabetes, retinal and progressive neurological degeneration. We describe genotypes and phenotypes at diagnosis, and disease evolution of seven Italian patients. Methods: Anagraphical, biochemical, genetic, clinical and instrumental data were collected at diagnosis and during a long-term follow-up. Mutations, ferroxidase activity and Western Blot analysis of ceruloplasmin were performed according to standard protocols. Results: Three mutations were already described (p.Phe217Ser, deletions of exon 11 and 12), p.Ile991Thr is a very rare variant, p.Cys338Ser and IVS6+1G > A were novel mutations. In silico analyses suggested they were highly likely or likely to be damaging. At diagnosis, 100% had microcytosis, 86% had mild-moderate anemia, low serum iron and high serum ferritin. Four (57%) had type 1 diabetes or glucose intolerance, 3/7 had neurological manifestations, and only one had early diabetic retinopathy. All but one underwent iron chelation therapy requiring temporary discontinuation because of anemia worsening. At the end of follow-up, three patients aggravated and 2 developed neurological symptoms; only two patients were free of neurological manifestations and showed mild or absent brain iron. Conclusion: Aceruloplasminemia phenotypes ranged from classical characterized by progressive neurologic derangement to milder in which signs of systemic iron overload prevailed over brain iron accumulation. Within this large heterogeneity, microcytosis with or without anemia, low serum iron and high serum ferritin were the early hallmarks of the disease. Therapeutic approaches other than iron chelation should be explored to reduce morbidity and improve life expectancy. © 2018 Elsevier Ltd

U2 - 10.1016/j.parkreldis.2018.02.036

DO - 10.1016/j.parkreldis.2018.02.036

M3 - Article

VL - 51

SP - 36

EP - 42

JO - Parkinsonism and Related Disorders

JF - Parkinsonism and Related Disorders

SN - 1353-8020

ER -