Atypical phenotype in a patient with ceruloplasmin mutations in the compound heterozygous state

Abstract

Aceruloplasminemia is an ultra-rare and fatal autosomal recessive disease with a long lasting neurological disabling period of life caused by mutations in ceruloplasmin gene. Disease phenotype is heterogeneous and variably characterized by iron-restricted erythropoiesis and microcytic anemia, hyperferritinemia with tissue iron accumulation in liver, pancreas and brain, diabetes, retinopathy and neurodegeneration. Although most heterozygotes are asymptomatic, they might present with significant neurological symptoms at some point in their lives. We report here a patient with hyperferritinemia and severe depressive disorder, harbouring two mutations in ceruloplasmin in the compound heterozygous state (p.Pro477Leu and p.Gly895Ala). Both mutations are classified as deleterious in silico, but in vitro functional study partially confirmed it. Our findings suggest that the two mutations cooperate in inducing low ceruloplasmin production in the range observed in aceruloplasminemia heterozygotes and raise the question whether this might increase patient's susceptibility to neurologic manifestations.