Introduction to aceruloplasminemia

Aceruloplasminemia is a rare genetic disorder, characterised by an accumulation of iron in the brain, and various other internal organs, caused by mutations of the ceruloplasmin (CP) gene.¹ If left untreated, aceruloplasminemia can lead to various neurological complications.²

Understanding iron metabolism

Iron: roles in oxygen transport and energy production

Aceruloplasminemia is characterised as an iron overload disorder. The regulation of iron in your body within a specific range is critical, as too much can result in organ damage, and too little results in iron-deficiency anaemia.^{3, 4} Iron is involved in making red blood cells, and so is a crucial mineral in the body. It is an important component of haemoglobin, the protein found in red blood cells that carries oxygen from your lungs around your body.^3,4 Additionally, iron is an important component of the process used by cells to generate energy.⁴

Normal iron processing: how the body absorbs, uses and stores iron

Iron is absorbed from foods including meat, eggs, and dark green vegetables through the small intestine ⁵. It then circulates in the bloodstream bound to transferrin, before most iron is delivered to the bone marrow to produce red blood cells, and some is delivered to other tissues for important cellular processes. Any excess iron is stored in organs such as the liver, in the form of ferritin, which is able to store iron and release it when it is needed.

The genetic cause of aceruloplasminemia

Aceruloplasminemia is caused by a rare mutation in the ceruloplasmin (CP) gene, which is critical for producing the protein ceruloplasmin, which is an important regulator of iron metabolism. It is inherited in an autosomal recessive pattern, meaning in order to show symptoms, an individual must receive a non-working gene from each parent, and if an individual inherits one working and one non-working gene from each parent, they will usually be asymptomatic.^1,2 The risk for aceruloplasminemia is the same for both males and females.¹

The defect in the ceruloplasmin gene in sufferers of Aceruloplasminemia results in a complete deficiency of the ceruloplasmin protein.²

Role of ceruloplasmin

Ceruloplasmin protein is responsible for storing and carrying copper around your body, but it also has an important role in iron metabolism and transport, essential for the normal movement of iron from cells into plasma.^{6, 7}

Copper-bound ceruloplasmin is required for the export of iron from tissues, involved in the conversion of iron from its ferrous (Fe2+) to ferric (Fe3+) form in plasma since the ferric form of iron is required for binding to transferrin, and iron transport. Without functional ceruloplasmin, iron cannot be transported out of cells, resulting in an excessive build-up. Normal iron transport can be maintained with as little as 5% normal ceruloplasmin levels, but aceruloplasminemia results in a complete deficiency, hence the characteristic iron overload-related symptoms.²

Pathophysiology of aceruloplasminemia

The deficient levels of functional ceruloplasmin mean that iron cannot be converted into a usable form for transport, and so iron becomes trapped in cells.¹ This results in an accumulation of iron in the brain and other organs of the body, such as the liver and pancreas which leads to damage to the tissues of the affected organs, and hence the symptoms of aceruloplasminemia.¹ Too much iron in organs leads to tissue damage due to oxidative stress.

Organ-specific effects

Brain: resulting in neurological symptoms due to iron accumulation in the basal ganglia

In most patients with aceruloplasminemia, iron accumulates within the basal ganglia, which is a part of your brain responsible for processing information involved in involuntary movements, coordination and cognition.¹ This results in a range of neurological symptoms that vary based on the extent of iron accumulation as well as the exact location of accumulation within the basal ganglia.¹

Neurological symptoms can include:¹

• Movement disorders: tremors, chorea (rapid, involuntary, jerky movements) and dystonia, which refers to a group of muscle disorders characterised by involuntary muscle contractions forcing the body into abnormal, and sometimes painful movements and positions
• Some affected individuals develop symptoms resembling Parkinson’s disease, such as tremors, abnormal slowness of movement and an inability to remain in a stable or balanced position.
• Cognitive impairment (can progress to dementia)
• Behavioural or emotional changes (such as depression) may also occur

Pancreas: leading to diabetes

Iron accumulation associated with aceruloplasminemia in the pancreas can lead to diabetes. The pancreas secretes hormones such as insulin, which are important for sugar breakdown. Damage to the pancreas may ultimately lead to diabetes mellitus, a condition where the body doesn’t produce enough or isn’t able to properly use insulin. The most noticeable symptoms of diabetes are excessive thirst and urination.¹

Degeneration of the retinas

The retinas are thin layers of nerve cells lining the inner surface of the eyes, important for sensing light and converting it into nerve signals, which are then relayed to the brain through the optic nerve.1 Iron deposition, or the diabetes that results from aceruloplasminemia can lead to damage to the retinal tissue.

Liver: dysfunction or cirrhosis

Hepatic (liver) iron overload can lead to cirrhosis, which is a condition where healthy tissue is replaced by scar tissue, which cannot function as normal healthy hepatic tissue does. If untreated, cirrhosis can lead to life-threatening liver failure.¹

Clinical manifestations

Symptoms of aceruloplasminemia vary greatly, and are not the same between one patient and another, even between members of the same family.

The age of onset varies, but the average age of diagnosis is 51.2, with a variation from 20s-60s.²

The most obviously spotted clinical manifestations are retinal degeneration, neurological symptoms, and diabetes mellitus.¹

However, anaemia, referring to low levels of circulating red blood cells, can often develop before the appearance of other symptoms commonly associated with aceruloplasminemia. This results in symptoms including fatigue, weakness, shortness of breath and pale skin.

Diagnosis of aceruloplasminemia

Aceruloplasminemia diagnosis is typically made by observations of the characteristic symptoms, and a variety of specialised tests, including:¹

• Blood tests to show:¹
  • Blood ceruloplasmin deficiency
  • Low concentrations of copper and iron in serum
• Magnetic resonance imaging (MRI) to show:¹
  • Iron deposits in the brain and liver 
• Genetic Testing to show:¹
  • Mutations in the CP gene: a definitive test

Treatment of aceruloplasminemia

It is important that the treatment of aceruloplasminemia is directed towards the specific symptoms that are present in each individual, due to the varied symptomatic nature of the disease.¹

Current therapies include

Iron chelation to reduce iron levels

Drugs such as deferoxamine reduce iron levels by binding to excess iron, allowing it to be dissolved in water and excreted from the body through the kidneys. However, it is yet to be confirmed whether this actually improves aceruloplasminemia symptoms. Ideally, iron chelation should be initiated before significant neurological symptoms have developed, as it is uncertain whether symptoms can be reversed.

Antioxidants

Antioxidants are believed to protect cells from oxidative damage, which is the main cause of organ tissue damage resulting from excess iron.

Management of diabetes

Using appropriate diet, tablets and insulin injections as required to manage blood sugar levels.

Genetic counselling

Recommended for affected individuals and their families, which involves advice to prospective parents concerning risks for their future children.

Neurological care 

Physical and occupational therapy can help manage movement disorders, and where required, mobility aids and speech therapy can be beneficial.

Future research: clinical trials and studies

Treatment with fresh frozen plasma, to restore normal levels of functional ceruloplasmin as well as deferoxamine, has been shown to decrease iron levels in the liver. Repeated transfusions of fresh frozen plasma have been shown to decrease iron levels in the brain in some cases.

Living with aceruloplasminemia

Careful management of aceruloplasminemia symptoms is essential for patients to be able to live a relatively normal, and healthy life. This involves regular monitoring of iron levels, diabetes management, and neurological care.

Early diagnosis and appropriate treatment, minimises complications and symptoms of aceruloplasminemia. Early diagnosis is important since it is a progressive condition, meaning symptoms worsen over time as iron builds up in various organs.

Coping with rare and progressive diseases such as aceruloplasminemia, can be emotionally and physically challenging for both patients and their families and friends. Support groups, either in person or online can be beneficial to provide a sense of community and understanding. Counselling or therapy, as well as patient support groups, can be hugely beneficial in reducing the emotional strain of aceruloplasminemia.

Summary

• Aceruloplasminemia is a rare, genetic, iron overload disorder
• Characteristic symptoms include neurological symptoms, diabetes mellitus and degeneration of the retinas
• With careful monitoring and treatment of symptoms, patients can maintain a high quality of life