What is Aceruloplasminemia?

Aceruloplasminemia is an inherited, rare disorder. The main symptom of this disorder is a lack of ceruloplasmin protein. Patients diagnosed with aceruloplasminemia cannot produce this protein due to a genetic mutation of the ceruloplasmin gene (CP gene). Ceruloplasmin is a protein which helps with iron transportation in the blood. The distribution of iron throughout the patient's body is insufficient, leading to iron accumulation in the liver, pancreas, and brain. The accumulated iron then causes damage to these organs. Also, brain areas such as the retina and basal ganglia are affected. This leads to neurological problems with vision and movement. Diabetes and retinal degeneration caused by iron deficiency are also common.¹

How is Aceruloplasminemia diagnosed?

A clinical examination can diagnose aceruloplasminemia. The examination consists of a variety of specialised tests, such as:

• Blood tests (to check levels of ceruloplasmin and iron)
• Magnetic resonance imaging (MRI) of the brain and liver (to check where and how the iron accumulates)
• Genetic testing (to demonstrate the mutations in the CP gene)²

Genetic basis of Aceruloplasminemia

What is the CP gene?

The CP gene, placed on the 3rd chromosome helps with the creation of the ceruloplasmin protein. This gene aids with the production of ceruloplasmin. The ceruloplasmin protein is important for the distribution of iron in the human body. Patients with aceruloplasminemia do suffer from a genetic mutation of the CP gene. The CP gene mutation often results in the production of a malfunctioning or absent ceruloplasmin protein.

There are several different types of CP gene mutations:

• Missense mutations are mutations that cause changes in “DNA building blocks” (nucleotides). These changes lead to alterations in the “protein building blocks” (amino acids), changing the final protein product and leading to possible medical issues¹
• Nonsense mutations are mutations that cause an early stop signal in gene expression. This results in a shortened, non-working ceruloplasmin protein¹
• In frame-shift mutations, cells add or delete one or more "DNA building blocks" (nucleotides). This alters the reading frame of the gene and results in the production of a completely different protein³
• Splicing mutations causes changes in how the gene reads and puts together instructions. This results in the production of an abnormal ceruloplasmin protein¹

How can Aceruloplasminemia be inherited?

Aceruloplasminemia is an autosomal recessive disorder, meaning that, both parents must contribute one copy of the mutated gene to a non-sex chromosome for the condition to manifest. Thus, for aceruloplasminemia, two copies of a mutated CP gene on the 3rd chromosome need to be present. Aceruloplasminemia is a very rare disorder. Children born to parents with the mutated CP gene have a 25% chance of developing aceruloplasminemia, a 50% chance of carrying a mutated CP gene but not developing symptoms, and a 25% chance of not developing the condition and not carrying the mutated CP gene.⁵

Why are molecular and genetic testing useful?

Genetic testing is crucial for the diagnosis of aceruloplasminemia. It can also serve as a prevention tool allowing early intervention and management to identify potential risks for the offspring. Common types of genetic tests used for diagnosis of aceruloplasminemia are genomic sequencing, and deletion/duplication analysis. Genomic sequencing analyzes a DNA sample collected usually from drawn blood. It looks at the entire genetic code of a person (genome), and by doing that it detects variations which cause conditions such as aceruloplasminemia.⁶ Yet, genomic sequencing can be inaccurate in detecting and explaining complex genetic changes, such as deletions and duplications, that overlap between the two copies of the same gene. This is where the deletion and duplication analysis come into play. Deletion and duplication analysis is a complementary method to genomic sequencing, it analyzes fragments of the genetic code to determine complex genetic changes and measures their exact size.⁷

How can Aceruloplasminemia be treated?

Iron chelators

Aceruloplasminemia can currently be treated with iron chelators. Iron chelators are drugs which help remove excess iron from the body. Examples of used iron chelators are: deferoxamine, deferasirox, or deferiprone. These drugs are ineffective in preventing or reversing the neurological symptoms of aceruloplasminemia.⁸

Alternative therapies

Alternative therapies such as zinc supplements, can help to block iron absorption. Some aceruloplasminemia patients use antibiotics like minocycline while others try vitamins E and C in combination with iron chelators. Doctors found that transfusing frozen plasma containing the missing ceruloplasmin protein was helpful. However, long-term use of these transfusions can be dangerous.⁸

Promising new treatments

Recent research also explored some potential new treatments. Animal studies on enzyme replacement therapy providing the missing ceruloplasmin protein have been done and they found a potential for future application on humans. Gene therapy that would correct underlying genetic problems of aceruloplasminemia, is in the early stages of research.⁸

How is Aceruloplasminemia inherited?

Aceruloplasminemia is an autosomal recessive disorder. This means that for someone to develop this condition 2 copies of a mutated CP gene on the 3rd chromosome need to be present. Children born to parents with the mutated CP gene have a 25% chance of developing aceruloplasminemia, a 50% chance of carrying a mutated CP gene but not developing symptoms and a 25% chance of not developing the condition and to not carrying the mutated CP gene.

Summary

Aceruloplasminemia is a rare genetic disorder which develops when two copies of the mutated CP gene on the 3rd chromosome are present (each passed from one parent). Even in a case where both parents carry the mutated CP gene, only 25% of their offspring is likely to develop the condition. Due to the CP gene mutation, there is a lack of ceruloplasmin protein. This protein is crucial for iron transportation in the body and its malfunctioning leads to the accumulation of iron in certain organs, iron accumulation then causes neurological issues with vision and movement. Conditions such as diabetes and retinal degeneration, are also often developed. Aceruloplasminemia can be diagnosed by blood tests, MRI, and most importantly, genetic testing. Researchers are still looking for an effective cure for aceruloplasminemia. Currently, iron chelators and alternative therapies are used to remove excess iron from the body.