The Phenotypic Spectrum of Patients with Genetic variants in Ceruloplasmin

Background Aceruloplasminemia (ACP) is a rare autosomal recessive disorder of iron metabolism and belongs to the heterogeneous group of neurodegenerative diseases with iron accumulation (NBIA). Patients typically present with diabetes mellitus, retinal degeneration and neurological symptoms. Characteristic biochemical findings including hyperferritinemia, low transferrin saturation and a decreased ceruloplasmin protein concentration. Aceruloplasminemia is caused by recessive mutations in the majority of patients but patients with simple heterozygosity have been reported.

Methods Ceruloplasmin gene (CP) sequencing was performed in a cohort of 186 patients with unexplained hyperferritinemia or decreased concentration of ceruloplasmin in plasma. Demographic, clinical and biochemical parameters of patients carrying pathogenic CP mutations and tissue iron concentrations in the brain and the liver analyzed by R2* magnetic resonance imaging (MRI) were retrospectively assessed.

Results Here we report on a cohort of 21 patients of which four patients are compound heterozygous and 17 are heterozygous for likely pathogenic variants or variants of unknown significance in CP. Twelve patients showed increased hepatic iron concentration and three patients had iron accumulation in the brain. One patient had been misdiagnosed as WD and copper chelation could be safely stopped.

Conclusion Patients with genetic variants in CP can present with a spectrum of conditions ranging from asymptomatic hyperferritinemia to severe and progressive neurodegeneration. The present study highlights that patients with heterozygous CP can also be misdiagnosed as Wilson disease or hemochromatosis.

Publication History

Article published online:
01 September 2021