Early diagnosis of aceruloplasminemia in infancy through NGS sequencing

Séverine CUNAT1, Alexandra GAUTHIER VASSEROT2, Philippe JOLY3, Muriel GIANSILY BLAIZOT1, Patricia AGUILAR MARTINEZ11

1Laboratory of hematological biology and expert center on rare iron disorders, Hôpital Saint Eloi, CHU of Montpellier, Montpellier, France
2Institut d’hématologie et d’oncologie pédiatrique, Hospices Civils de Lyon, Lyon, France
3Hospices Civils de Lyon, Service de biochimie et de biologie moléculaire Grand Est, Bron, France

Aceruloplasminemia is a rare autosomal recessive disorder of iron metabolism, linked to mutations in the CP gene. Most diagnoses are made in adulthood in the context of neurological manifestations and diabetes mellitus. The disease is usually accompanied by moderate microcytic anemia, which is not the main clinical feature.



We report here the discovery of aceruloplasminemia in a 2-year-old girl.



The child was initially examined at the age of 6 months for microcytic hypochromic anemia without overt iron-deficiency. Nevertheless, oral iron administration increased blood hemoglobin from 6 to 8 g/dL, and then, stayed at this value. There was no dysmorphic syndrome and no mental retardation nor growth delay. Globin gene studies were normal. Bone marrow examination ruled out a sideroblastic anemia, but showed severe iron depletion. Serum ferritin was elevated (>100 µg/L), serum iron and transferrin saturation were very low, with no biological inflammatory syndrome.



Analysis of a NGS panel of genes involved in iron and red blood cell disorders identified a homozygous CP gene variant (p.(Glu587ArgfsTer37)). This variant is not referenced in literature nor in databases. However, it is located in one of the cupredoxin protein domains. It results in a frameshift from codon 587 onwards with a stop codon 37 amino acids later. This change is therefore likely to significantly alter the protein's function and ferroxidase activity. 



The question now is what treatment could be given to this child, to avoid the constitution of brain iron overload which is key to the prognosis of the disease.

 

Acknowledgements: ERN-EuroBloodNet