Introduction

Aceruloplasminemia is a rare, hereditary condition that is recognised by a large accumulation of iron in certain internal organs, including the brain.¹ It affects approximately 1 in 2 million people, leading to a restricted comprehension of the condition.² Children are less commonly affected, and this disordertypically becomes apparent in adulthood between the ages of 20 and 60 years old.¹ Despite being a genetic disorder, severity of symptoms can vary among people of the same family. Mutations of the ceruloplasmin gene, which is responsible for transporting iron from organs and tissue into the blood, produces symptoms associated with this condition. These mutations are inherited in an autosomal and recessive pattern.^1,3 Aceruloplasminemia is classed as both a neurodegenerative with iron accumulation in the brain (NBIA) and iron overload disorder.¹

Mechanism of iron overload

The iron overload that characterises aceruloplasminemia is caused by a homozygous mutation in the recessive ceruloplasmin (CP) gene.⁴ This gene codes for the CP protein, and the mutation present in aceruloplasminemia leads to its defective production. This results in iron overload, as CP is essential in maintaining iron homeostasis. It is a ferroxidase that catalyses the oxidation of iron (Fe²⁺) into Fe³⁺, which is crucial in oxygen transport as only Fe³⁺ can be taken in by the main blood iron transport protein, transferrin. If deficiencies in CP are present, less Fe³⁺ will be present to be transported out of cells, causing an Fe²⁺ accumulation within cells.²

Secondary function of ceruloplasmin

CP not only enables iron transport out of cells, it also has antioxidant properties. This is important because Fe²⁺ is a reactant within the Fenton reaction, leading to the formation of dangerous reactive species such as hydroxyl groups. CP would normally prevent the formation of these reactive species, as Fe²⁺ is oxidised in the Fenton reaction and CP has antioxidative properties.² Therefore, ceruloplasmin deficiencies can lead to both high levels of iron accumulation and harmful species formation.

Clinical manifestations of aceruloplasminemia

The main symptoms associated with aceruloplasminemia are listed below:^1,5

• Anaemia
• Retinal degeneration
• Diabetes mellitus
• Neurological symptoms such as ataxia (inability to coordinate voluntary movements) and dysarthria (difficulty speaking)

As aceruloplasminemia is caused by dysfunction associated with CP, the associated symptoms are related to an accumulation of iron in certain organs and nervous tissue. 

Typically, the first symptom to manifest is anaemia, caused by a lack of circulating iron due to its accumulation in organs and tissues such as the retina, pancreas and basal ganglia.^1,5 While retinal degeneration has been associated with aceruloplasminemia itself, it has been suggested that it can also be a symptom of diabetes which develops as a result of aceruloplasminemia. 

Diabetes mellitus is caused by increased iron deposition within the pancreas, leading to disruption to insulin production. This affects the body’s ability to regulate blood sugar levels, leading to diabetes. 

Iron can also accumulate within the brain and, most commonly, aceruloplasminemia is associated with iron accumulation within the basal ganglia. As the basal ganglia is associated with the motor cortex, neurological symptoms such as ataxia and dysarthria are common. However, aceruloplasminemia can also lead to emotional and cognitive dysfunction, which can eventually progress into dementia.¹

Chelation therapy

Chelation therapy is often used to treat metal poisoning and aims to remove the toxic metal from the body to prevent harm. It involves the use of ‘chelators’, which bind to the harmful metals and detoxify them while also enabling the body to more easily excrete the metal. Chelators contain polydentate ligands which surround the toxic metal and form covalent bonds with it to form a chelate - the more easily excreted molecule. Common chelators include dimercaprol and deferoxamine, and can be administered intravenously, intramuscularly, or orally. 

Chelation therapy began during World War II when chemists searched for an antidote for an arsenic-based chemical weapon.⁶ It was discovered that dimercaprol had these properties and following this, other chelators were found, and chelation therapy started becoming a more common therapy for metal poisoning.⁷

In the context of aceruloplasminemia, chelation therapy is a commonly used treatment. This is because treatment of aceruloplasminemia is largely based on the control and management of iron overload which can be managed by chelation therapy. Iron chelators bind to excess systemic iron, enabling it to be water soluble and excreted from the body through the kidneys. 

The goals of chelation therapy in treating aceruloplasminemia are to reduce the iron accumulation within the body, alleviate any negative symptoms and prevent further organ or tissue damage.¹ Only certain chelators work in the context of removing iron and some examples of these are deferoxamine, deferiprone and deferasirox. These chelators are effective in reducing systematic iron accumulation, however they are not the perfect treatment.²

Limitations and challenges of chelation therapy in aceruloplasminemia

As mentioned, chelation therapy has factors that must be considered. These include but are not limited to, the clinical efficacy of the treatment, potential side effects and the adherence to dose monitoring. The efficacy of therapy can be questioned as certain chelates are less effective at crossing the blood brain barrier, potentially leading to lower therapeutic efficacy on neurological symptoms.^2,8 

Some research suggests that chelation therapy is effective only before the manifestation of neurological symptoms, while others found that chelation therapy does not impact these symptoms.^2,9 This variability raises concerns about its neurological benefit, especially as the disease progresses.

Although chelation therapy is effective in reducing systemic iron levels, its ability to impact blood glucose regulation and neurological outcomes remains uncertain. This limited efficacy is also coupled with potentially limited long-term use. This is because while iron accumulation will be reduced, blood iron levels do not increase, meaning that chelation therapy will not treat anaemia symptoms, which is also a common feature of aceruloplasminemia. 

Occasionally, supplements such as vitamin E and C are taken alongside chelation therapy to minimise oxidation reactions.² While potentially beneficial, this adds further complexity to the treatment plan.

Chelation therapy also present practical challenges:

• Time consuming infusions
• Frequent monitoring
• Emotional and physical burden on patient

Aside from efficacy considerations, incomplete symptomatic treatment and the time consuming nature of the treatment, the usability of chelation therapy is also limited by its potential side effects. These include feelings of: 

• Nausea
• Agranulocytosis
• Gastrointestinal problems
• Arthropathy 

These factors draw into the argument of the effectiveness of this treatment and whether it should be used, prompting further discussion around its long term role in treatment.^8,10

Alternative treatments and integrated strategies

There are alternative treatments aside from chelation therapies and these include phlebotomies (blood removal), dietary changes, antioxidants, ‘frozen fresh plasma’ administration and potentially, in the future, gene therapies.² 

Phlebotomies could be a less time consuming alternative to chelation therapies; however, as anaemia is commonly associated with aceruloplasminemia like with chelation therapy, phlebotomies are often contraindicated.^2,5 

Dietary changes and antioxidants both serve to reduce potential damage caused to cells by the formation of free radicals through the Fenton reaction. This is achieved by either reducing the consumption of iron-rich foods, such as red meat, or by antioxidants preventing the oxidation reaction from occurring. 

‘Frozen fresh plasma’ administration aims to temporarily restore circulating CP levels and it has been shown to have positive impacts on both neurological and systemic iron symptoms of patients.² 

Families that have a history of aceruloplasminemia are recommended to seek genetic screening to catch the condition as early as possible.¹ 

Chelation therapy can work alongside some of these treatments and some chelates are additive, enabling different iron stores to be targeted, opening the doors for more personalised medicine.¹¹ While alternative therapies are available, combining multiple treatments may be the best approach. By controlling iron intake, seeking chelation therapy and treating other symptoms, such as diabetes with insulin, the condition can be appropriately managed.

Summary

Aceruloplasminemia is a genetic disorder that affects the body’s levels of iron, primarily in the brain. If an individual shows any symptoms mentioned, they should consult a healthcare professional, as the earlier this condition is recognised, the more treatable it is. Treatment may include therapies such as chelation therapy, or lifestyle changes to reduce iron intake. There is current and ongoing research into gaining a deeper understanding of what this condition entails, however a high quality of life can be maintained for a patient.