Aceruloplasminemia: A Severe Neurodegenerative Disorder Deserving an Early Diagnosis

Abstract

Aceruloplasminemia (ACP) is a rare, adult-onset, autosomal recessive disorder, characterized by systemic iron overload due to mutations in the Ceruloplasmin gene (CP), which in turn lead to absence or strong reduction of CP activity. CP is a ferroxidase that plays a key role in iron export from various cells, especially in the brain, where it maintains the appropriate iron homeostasis with neuroprotective effects. Brain iron accumulation makes ACP unique among systemic iron overload syndromes, e.g., various types of genetic hemochromatosis. The main clinical features of fully expressed ACP include diabetes, retinopathy, liver disease, and progressive neurological symptoms reflecting iron deposition in target organs. However, biochemical signs of the disease, namely a mild anemia mimicking iron deficiency anemia because of microcytosis and low transferrin saturation, but with "paradoxical" hyperferritinemia, usually precedes the onset of clinical symptoms of many years and sometimes decades. Prompt diagnosis and therapy are crucial to prevent neurological complications of the disease, as they are usually irreversible once established. In this mini-review we discuss some major issues about this rare disorder, pointing out the early clues to the right diagnosis, instrumental to reduce significant disability burden of affected patients.

Keywords: Aceruloplasminemia; iron metabolism; iron overload disease; neurodegeneration with brain iron accumulation; rare anemias.

FIGURE 1

(A) Different functions of soluble and membrane-bound ceruloplasmin. Ferroxidase activity of membrane-bound CP is essential since only Fe³⁺ (but not Fe²⁺) can be incorporated into plasma transferrin, and then delivered to other cells (mainly erythroid precursors) via Transferrin Receptor 1 (TfR1). (B,C) Model of iron cross-talk between astrocytes and neuronal cells. (B) Ceruloplasmin is needed to oxidize Fe²⁺ into Fe³⁺, the only iron form that can be bound to transferrin for appropriate iron uptake by neurons through the transferrin receptor type 1 (TfR1). (C) Lack of ceruloplasmin leads to initial iron accumulation into astrocytes and starvation of neurons, with ensuing alteration of energetic metabolism and synthesis of neurotransmitters. This later stimulates the neuronal uptake alternative sources of iron, like non-transferrin-bound iron (NTBI), which is further toxic.

FIGURE 2

Clinical clues for ACP diagnosis. Percentages are taken from references (Miyajima and Hosoi, 1993–2018; Vroegindeweij et al., 2017; Pelucchi et al., 2018).