Introduction 

Aceruloplasminemia is a rare genetic disorder where there is a gradual build-up of iron in the brain and other internal organs.  Individuals affected by this disorder may experience the development of neurological symptoms that can affect cognitive ability, movement, and vision.  Symptoms of this disorder typically present during adulthood, between 20 and 60 years of age.¹ 

Aceruloplasminemia is caused by a mutation of the ceruloplasmin (CP) gene.  The CP gene is responsible for making a protein called ceruloplasmin, which helps move iron from the organs and tissue into the bloodstream.  The mutation of this gene is inherited in an autosomal recessive pattern, which means a copy of the mutated gene has been passed on from both parents.  There are approximately 40 different mutations of the CP gene that can cause aceruloplasminemia.²

Clinical features of aceruloplasminemia

Aceruloplasminemia is a very rare disorder that has been found to affect both men and women equally. The true incidence of this disorder is unknown due to many cases, unfortunately, being undiagnosed or misdiagnosed. 

Symptoms of aceruloplasminemia typically begin during adulthood, between the ages of 20 and 60 years, with the severity varying from one person to another. There are three main “tells”(primary indicators) that are associated with aceruloplasminemia, which are:

• Diabetes mellitus
• Neurological degeneration
• Retinal degeneration   

Some individuals affected by aceruloplasminemia may experience symptoms of anaemia, causing fatigue, weakness, shortness of breath, and pale skin. These symptoms often occur before the development of other more serious complications of aceruloplasminemia. 

Neurological symptoms

There are a variety of different neurological symptoms that can occur in individuals with aceruloplasminemia, caused by the accumulation of iron in the brain. The most common neurological symptoms are typically those that are similar to movement disorders, including:

• Difficulty coordinating voluntary movement (ataxia)
• Difficult with speech and slurring of words (dysarthria)
• Changes in behaviour 
• Decline in cognitive ability

Movement disorders caused by aceruloplasminemia often include muscle disorders that can force the body into abnormal and painful movements and positions caused by involuntary muscle contractions, known as chorea. Other muscle disorders caused by aceruloplasminemia include tremors and dystonia.  Blepharospasms are a type of dystonia that affects the muscles around the eyes, causing them to involuntarily spasm and contract.³

In certain cases, affected individuals may experience symptoms like those of Parkinson’s disease, sometimes referred to as Parkinsonism. These symptoms may include:

• Tremors 
• Slow movements 
• Difficulty in staying still or maintaining a stable position

Further neurological symptoms can cause affected individuals to develop cognitive impairment, which may progress to dementia.⁴ Behavioural and emotional changes are common and may result in the development of depression or other mental health disorders.⁵

Hepatic symptoms

Hepatic refers to the liver. Hepatic iron overload or hemochromatosis is a symptom of aceruloplasminemia due to the gradual build-up of iron inside the liver.⁶ This can cause symptoms like: 

• Fatigue
• Weakness
• Weight loss
• Joint pain
• Brain fog
• Mood swings and emotional changes, like depression or anxiety

However, liver damage does not occur as a result of iron build-up in individuals with aceruloplasminemia. 

Ophthalmologic symptoms

Ophthalmology refers to the study or branch of medical science that deals with the structure, diagnosis and treatment of the eyes. 

Aceruloplasminemia is associated with progressive retinal degeneration.  The retina is the thin layer of nerve cells that covers the inner layer of the eyes, which react to sunlight through nerve signals sent to the brain by the optic nerve.  Retinal degeneration can either be caused by iron deposits elsewhere in the body or be a symptom of diabetes mellitus, which is another complication of aceruloplasminemia.  Symptoms of aceruloplasminemia-related retinal degeneration may include:

• seeing floaters or specks
• blurry or distorted vision
• Decreased peripheral vision
• vision loss

Haematological symptoms

Anaemia is often the first complication of aceruloplasminemia, occurring before more serious signs and symptoms begin to develop in adulthood. Anaemia is caused by a low amount of circulating red blood cells throughout the body and can cause symptoms such as:

• Fatigue
• Muscle weakness
• Shortness of breath
• Dizziness when standing up after sitting or lying
• Pale skin

Microcytic anaemia is the type of anaemia most commonly associated with individuals that suffer from aceruloplasminemia. This type of anaemia is characterised by abnormally small red blood cells caused by a lack of haemoglobin, the protein responsible for carrying oxygen throughout your body. There is a lack of iron circulating in the bloodstream of aceruloplasminemia patients because of the excessive accumulation of iron stored in other parts of their body, leading to an overall deficiency.⁷ 

Diagnosis of aceruloplasminemia 

Diagnosis of aceruloplasminemia is carried out by identification of the characteristic symptoms, patient and family history, and thorough clinical evaluation of specialised tests, such as a blood test, genetic testing, and magnetic resonance imaging (MRI).

• Blood tests can help to identify if there are low levels of circulating copper and iron in the bloodstream and determine the presence of ceruloplasmin, a protein that helps to carry and store copper in your body
• Genetic testing is used to check for mutations in the CP gene and is regarded as the definitive diagnostic test in identifying aceruloplasminemia
• MRI scans are used to reveal characteristics of aceruloplasminemia in the brain and liver, using a magnetic field and radio waves to produce a cross-sectional image of the specific organs and tissues that may have an accumulation of iron⁸

It is common for your GP or specialist doctor to carry out a variety of tests in order to diagnose you correctly. As there are disorders with similar symptoms, your doctor may compare your symptoms to those of similar disorders in case of a differential diagnosis, then carry out further tests for confirmation. 

Summary

Aceruloplasminemia is a rare genetic disorder characterised by a gradual build-up of iron within the internal organs of the body. Those affected by this disorder may initially experience symptoms of anaemia, like fatigue, muscle weakness, and pale skin, before they experience more serious symptoms elsewhere in their body. A build-up of iron in the brain can lead to progressive and degenerative neurological complications, resembling those of motor disorders, where the individual may find it difficult to coordinate their movements. Further complications may include retinal degeneration that may progress to vision loss, along with hepatic iron overload in the liver causing symptoms like fatigue, weight loss, and mood changes.

Diagnosing aceruloplasminemia requires a thorough assessment of symptoms, medical history, and specialized testing. Genetic testing is the most reliable method, as it directly confirms mutations in the CP gene. Blood tests can further support the diagnosis by detecting abnormalities in ceruloplasmin, copper, and iron levels. Additionally, MRI scans provide valuable insights by revealing iron accumulation in the brain and liver. By combining these diagnostic tools, healthcare professionals can accurately identify the disorder and initiate appropriate treatment strategies to manage its effects.