Introduction

Aceruloplasminemia is a rare autosomal recessive disorder that occurs when iron is clustered in the human brain and other body organs, also known as NBIA (neurodegeneration with brain iron accumulation). It is a result of mutations in the ceruloplasmin gene (CP), which is inherited through generations. Such genetic diseases are caused by an individual receiving a non-working gene from each of their parents. If an individual receives only one non-working gene overall, they will still carry the genetic disease, but may not show symptoms. However, for aceruloplasminemia, despite having only one non-working gene, in some cases, it could lead to cerebellar ataxia, which is also known as a disease that involves difficulties in coordinating movements.

The function of the CP gene is to generate sufficient enzyme ceruloplasmin, which is essential for the transportation of iron around the body. The mutation of this gene leads to an insufficient amount, resulting in clusters formed in organs in the body. It specifically accumulates in a specific brain region known as the basal ganglia.

To diagnose aceruloplasminemia, doctors often use imaging techniques like MRI, which is based on the absence of serum ceruloplasmin and an increased ferritin level. In this article, a detailed analysis of how different imaging devices or techniques are used to diagnose, treat, and aid patients who suffer from aceruloplasminemia.¹

Pathophysiology of aceruloplasminemia

There are approximately 40 different gene mutations within the CP gene that cause aceruloplasminemia. Certain mutations replace one amino acid in the ceruloplasmin protein with a different amino acid, leading to an unstable protein that rapidly degrades. Other mutations cause the production of a truncated, nonfunctional protein or block the secretion of the protein from the cells where it is synthesised. The lack of functional ceruloplasmin disrupts iron transport, resulting in iron accumulation, neurological dysfunction, and other characteristics of aceruloplasminemia.²

Ceruloplasmin (CP) is a copper-containing enzyme critical for maintaining iron balance in the brain, liver, pancreas, and retina. In the brain, CP helps protect neurons from iron deficiency and oxidative damage due to iron overload. When CP ferroxidase activity is impaired, cells retain iron abnormally, leading to oxidative damage. CP has two isoforms produced by alternative splicing: a soluble form in the plasma and a GPI-anchored membrane form. In aceruloplasminemia, early neuronal damage may occur because neurons cannot obtain iron from CP-deficient astrocytes, causing neurodegeneration from iron buildup, oxidative stress, loss of astrocytes, and the uptake of toxic iron sources by neurons.³

Patients suffering from aceruloplasminemia often experience the following symptoms:

1. Ataxia
2. Involuntary muscle control
3. Cognitive decline
4. Retinal degradation
5. Iron-refractory anaemia

Imaging techniques

Scientists have relied on several techniques.to diagnose aceruloplasminemia over the years.

They are the following:

1. Magnetic Resonance Imaging (MRI) 

MRIs utilise powerful magnets to create a strong magnetic field, causing the protons in the body to align with this field. When a radiofrequency pulse is applied, these protons become excited and move out of alignment, resisting the magnetic pull. After the radiofrequency pulse stops, MRI sensors detect the energy released as the protons return to their original alignment with the magnetic field.

2. Computed Tomography (CT)

A CT scan is a medical imaging technique that combines X-rays and computer technology to create detailed pictures of the internal body. It provides clear images of various body parts, like fat and blood vessels.

3. Ultrasound 

An ultrasound scan, also known as a sonogram, is an imaging method that uses high-frequency sound waves to generate images of the inside of the body. This is achieved by sending a signal from a transducer and then receiving the reflected signal to create the image.

Researcher Firdaous Touarsa conducted a study on a 53-year-old person assigned female at birth (AFAB). First, approaching the patient with a CT scan to understand her disorder, it revealed hypodense lesions in the basal ganglia bilaterally. Second, MRI scans revealed increased signal intensity on T2-weighted images (T2WI), decreased signal intensity on T1-weighted images (T1), and diffusion-weighted imaging (DWI) in regions that appeared hypodense on CT scans. These regions are surrounded by decreased signal intensity on T2WI and involve both sides of the cortex, as seen in Figure 1.

Figure 1

When transferring MRI from the brain to the liver, it has been noticed that there is an immense amount of iron deposition in the liver in comparison to the spleen. Similarly, in December 2007, another female aged 57 was instructed to conduct an abdominal MRI, revealing increased signal due to an increase in iron in Figure 2.⁴

Figure 2

Furthermore, a further study conducted by Chimaobi M Anugwom reveals the usage of ultrasound and MRI to diagnose aceruloplasminemia. It is vital to note that the abdominal ultrasound showed the presence of gallstones without signs of inflammation or dilation of the bile ducts. Whereas for magnetic resonance cholangiopancreatography (MRCP), it did not detect any abnormalities in the bile ducts. It is essential to use more than one imaging technique to verify the diagnosis in different parts of the body. The advantage of using ultrasound is that it is non-invasive and cost-effective.⁵

Emerging imaging techniques

Many emerging imaging techniques help diagnose aceruloplasminemia. One of the examples is by using PET scans. A PET CT scan works by injecting a small dose of radioactive glucose into a vein. Using a PET scanner, images show where glucose is utilised in the brain.

Malignant tumour cells appear brighter in these images because they are more active and consume more glucose than normal cells. Iron deposition correlates with increased metabolic activity, which shows up on the PET CT scan with the radioactive glucose.⁶

Moreover, fusion imaging has gained popularity by creating an overlay of images created by different imaging devices in the same spatial coordinate space. This way, scientists, radiologists, and medics identify regions of iron deposition and other abnormalities.⁷

Diagnostic and prognostic implications

Like any other disease, the earlier the diagnosis, the better the handling. It can be diagnosed via MRI, CT scan, and ultrasound. Ultimately, any body check-ups with results coming back revealing the absence of ceruloplasmin in the blood, alongside a combination of low serum copper levels, low serum iron levels, elevated serum ferritin levels and excessive iron accumulation in the liver can suggest the possibility of aceruloplasminemia. However, to confirm and proceed further, genetic testing must be done.⁸ The prognosis of aceruloplasminemia can often be observed from incidents such as cardiac failure, which is a result of the buildup of iron.

Summary

In conclusion, aceruloplasminemia is a rare genetic disorder, often caused by the deposition of iron in the brain or any other organs. This results in symptoms like fatigue and breathlessness. Accurate diagnosis relies on a combination of advanced imaging techniques, such as MRI, CT scans, and ultrasounds, alongside genetic testing. Emerging methods like PET scans and fusion imaging enhance diagnostic precision by highlighting areas of iron deposition and metabolic activity. Early diagnosis is critical for effective management, allowing for timely interventions that can slow symptom progression and improve patient outcomes. Genetic testing remains essential for confirming the diagnosis and understanding familial risks. As imaging and diagnostic technologies advance, they hold promise for more precise, comprehensive detection and management of aceruloplasminemia, offering new hope for affected individuals and their families.

FAQs

Can aceruloplasminemia be cured? 

Individuals diagnosed with aceruloplasminemia may be treated by consuming a drug called desferrioxamine, which is also an iron chelator. Its function is based on the drug being able to bind itself to any excess iron in the organs, removing it and reducing the iron level in the body.

What resources are available to individuals diagnosed with aceruloplasminemia?

Other than drugs that can treat the disease, clinics offer support groups for patients who are diagnosed with aceruloplasminemia as well as their families.

How many people are affected?

A study conducted in Japan estimated that aceruloplasminemia affects 1 in 2 million adults.