Overview

Aceruloplasminemia is a rare inherited condition characterised by iron accumulation in the brain and other internal organs such as the liver and pancreas.¹ This is caused by absent or dysfunctional ceruloplasmin (CP), a copper-containing protein involved in maintaining healthy iron levels in the body.²

The prevalence of aceruloplasminemia is estimated to be 1 in 2 million in the Japanese population.³ Although the disease has been reported in other geographical locations, further research is necessary to establish its distribution in non-Japanese populations. 

Aceruloplasminemia arises from autosomal recessive genetic mutations.⁴ Therefore, children of two individuals carrying the disease-associated gene will have a 1 in 4 chance of being affected, a 1 in 4 chance of being unaffected, and a 1 in 2 chance of not having the disorder but carrying the gene. 

Previous cases have often reported significant diagnostic delays in aceruloplasminemia.^3,5 This may be due to a lack of awareness about the disorder and challenges in its differential diagnosis, which involves distinguishing aceruloplasminemia from other possible conditions.

Early diagnosis and medical intervention for individuals affected by aceruloplasminemia are crucial to avoid irreversible organ damage.

Clinical presentation of aceruloplasminemia

The onset of clinical symptoms of aceruloplasminemia typically occurs in late adulthood, ranging between 30 to 70 years of age.4,5 In aceruloplasminemia, the absence of CP regulation of iron levels in the brain leads to neurodegeneration, on top of iron overload and toxic damage in other internal organs, particularly the liver, pancreas and retina. 

Studies of Japanese aceruloplasminemia patients have reported a clinical triad consisting of diabetes, retinal degeneration, and neurological signs such as dementia (decline in brain function) and ataxia (movement disorders that affect coordination and balance).^1,3 These neurological issues can lead to behavioural anomalies, including forgetfulness and involuntary movements. 

In contrast, non-Japanese patients tend to exhibit this clinical trial at a lower rate.^5,6 Instead, they more commonly present with microcytic anaemia, characterised by smaller-than-normal red blood cells and a lower-than-normal count, prior to the onset of diabetes and neurological symptoms.

Diagnosis criteria

A lack of consistent descriptions of aceruloplasminemia cases, combined with its low prevalence, has made it challenging to establish clear diagnostic criteria for the disorder. Currently, diagnosis is based on a combination of clinical, biochemical, radiologic, and genetic assessments.

Biochemical characteristics that may point towards aceruloplasminemia include:^4,5

• Low CP concentration in the blood
• Low copper concentration in the blood
• Low iron concentration in the blood
• High iron concentration in the liver, which may be confirmed through a liver biopsy (examination of tissue sample)
• High ferritin concentration in the blood, in which ferritin is a protein that stores iron
• Low transferrin saturation (TSAT) levels, in which transferrin is a protein produced by the liver that moderates iron transport in the blood 

Radiographic examination is typically conducted via magnetic resonance imaging (MRI), in which clear images of internal structures are obtained using magnetic fields and radio waves. Low intensities on MRI in the liver and brain are characteristic of aceruloplasminemia, due to iron deposits.^1,4,7 

Diagnosis of a proband, who is an individual identified to potentially have a genetic disorder despite having no family history, with the aid of genetic testing.⁴ This may be in the form of gene-targeted testing, which investigates selected genes for mutations, or genome sequencing, which scans the whole genome for potential disease-causing mutations.

Given the variance in clinical manifestations, anaemia, which may or may not be microcytic, low TSAT and high ferritin levels in the blood have proven to be most effective for pre-symptomatic diagnosis of aceruloplasminemia.^3,5 

Differential diagnosis of aceruloplasminemia

Other disorders to consider in the differential diagnosis of aceruloplasminemia include:^1,2,3,4

• Wilson’s disease
  • An inherited disorder characterised by copper accumulation in body organs 
  • Similar symptoms include copper and CP deficiencies in the blood
  • This can be excluded by the presence of iron accumulation in the liver and brain 
• Hereditary haemochromatosis
  • An inherited disorder characterised by iron accumulation in the body
  • This can be excluded by elevated ferritin concentrations in the blood and low TSAT
• Ferroportin disease (Type 4 haemochromatosis)
  • An inherited disorder characterised by iron accumulation in the body 
  • Can be excluded by the presence of anaemia and a pattern of iron accumulation in the liver
• Atypical pantothenate kinase-associated neurodegeneration (PKAN)
  • An inherited movement disorder which causes involuntary movements due to iron accumulation in the brain
  • Can be excluded by evidence of iron accumulation in other body organs, such as the liver, as well as the development of diabetes and retinal degeneration
• Neuroferritinopathy
  • An inherited movement disorder which causes involuntary movements and ataxia due to iron accumulation in the brain
  • Can be excluded by evidence of iron accumulation in other body organs, such as the liver, as well as the development of diabetes and retinal degeneration
• Huntington’s disease
  • An inherited neurodegenerative disorder characterised by involuntary movements, memory lapses and behavioural anomalies due to early degradation of nerve cells in the brain
  • This can be excluded by evidence of iron accumulation in body organs such as the brain

Aceruloplasminemia can be differentiated from other iron metabolism disorders as it is the only disorder aside from neuroferritinopathy that results in iron accumulation in the central nervous system (CNS), which comprises the brain and spinal cord.²

Treating aceruloplasminemia

Aceruloplasminemia is commonly treated with iron-chelating agents that bind to iron, enabling its removal from organs where it has accumulated.^1,3,4 The most frequently used chelating agents are deferoxamine (or desferrioxamine), deferasirox, and deferiprone. Among these, deferiprone is the only one that can cross the blood-brain barrier (a layer of cells that protects the brain from damage), allowing iron to be removed from the brain.³

These iron-chelating agents have been shown to reduce ferritin levels in the blood and decrease iron accumulation in the liver. However, there is limited evidence proving their effectiveness in improving neurological symptoms and reducing iron accumulation in the brain. They have also been known to exacerbate existing anaemia symptoms in some cases.³

Administration of antioxidants such as vitamin E and zinc sulphate may be used in combination with iron-chelating agents to reduce organ damage.^3,4

Fresh-frozen human plasma (FFP) containing CP may also be administered alongside iron-chelating agents. Studies have shown that neurological symptoms can improve with repeated FFP treatments.^3,4

Studies in mice have shown that the administration of recombinant CP (a protein produced for therapeutic purposes) can cross the blood-brain barrier and reduce iron deposits in the brain. This presents a promising potential treatment option for the future.³

Summary

Aceruloplasminemia is a rare genetic disorder characterised by a loss of function or absence of ceruloplasmin (CP), a copper-containing protein that helps regulate iron levels in the body. Clinical signs of aceruloplasminemia include diabetes, retinal degeneration, movement disorders, dementia, and microcytic anaemia. 

The diagnosis of aceruloplasminemia involves assessing clinical, biochemical, radiologic, and genetic characteristics. Anaemia, low transferrin saturation (TSAT), and high ferritin levels are considered benchmarks for accurate early diagnosis. Other disorders, including movement and neurodegenerative disorders, should be considered in the differential diagnosis of aceruloplasminemia. These can be distinguished through biochemical and radiographic evidence. 

Iron-chelating agents are commonly used to treat aceruloplasminemia, sometimes in combination with antioxidants and fresh-frozen human plasma (FFP) to prevent further organ damage and mitigate neurological symptoms. Recombinant CP, which could be injected intravenously, shows promise as a potential treatment option, though further studies on human subjects are necessary.