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.

New mutation of the ceruloplasmin gene in the case of a neurologically asymptomatic patient with microcytic anaemia, obesity and supposed Wilson’s disease

“…The basic laboratory finding is a very low measurable concentration of ceruloplasmin in serum. Other laboratory findings include a low concentration of serum iron, low saturation of transferrin (10%), elevated concentration of serum ferritin and microcytic anaemia of light degree [18]. Visual examination is performed to diagnose peripheral degeneration of the retina [16].…”

Mitochondrial Dysfunction, Oxidative Stress and Neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)

“…Close to 70 mutations (missense, frameshift, splicing, nonsense) have been described in CP (HGMD ® Professional 2020.1; accessed 16 September 2020). Homozygous mutations are identified in the vast majority of patients, although compound heterozygosity may be also detected [ 170 ]. Even though inheritance is AR, heterozygous carriers may present with a milder clinical picture [ 171 ].…”

Genetic and Clinical Heterogeneity in Thirteen New Cases with Aceruloplasminemia. Atypical Anemia as a Clue for an Early Diagnosis

“…Aceruloplasminemia (ACP) (OMIM#604290, ORPHA48818) is an adult-onset rare autosomal recessive disorder due to mutations in the CP gene (3q24-q25) encoding ceruloplasmin (CP), a copper-containing ferroxidase involved in maintaining iron homeostasis [1,2]. The pathological basis of ACP includes mild microcytic anemia and iron overload in several tissues, which can lead to diabetes mellitus, liver disease, progressive neurodegeneration, and retinopathy [1].…”

“…ACP was first described in 1987 in a 52-year-old Japanese female suffering from retinal degeneration, diabetes mellitus, and blepharospasm [3]. Usually, the onset of clinical manifestations is around the fourth or fifth decade of life, while biochemical signs of mild microcytic anemia with low transferrin saturation (TSAT) and paradoxically high ferritin may be evident since childhood [2]. Its prevalence is estimated at about one per two million offspring in Japanese non-consanguineous marriages, while epidemiologic data in the non-Japanese population are substantially missing [1].…”