Aceruloplasminemia

Disease Overview

Aceruloplasminemia is a rare genetic disorder characterized by the abnormal accumulation of iron in the brain and various internal organs. Affected individuals develop neurological symptoms including cognitive impairment and movement disorders. Degeneration of the retina and diabetes may also occur. Symptoms usually become apparent during adulthood between 20 and 60 years of age.

Aceruloplasminemia is caused by changes (disease-causing variants) in the ceruloplasmin (CP) gene. This condition is inherited in an autosomal recessive pattern.

Aceruloplasminemia is classified as a neurodegenerative disorder with brain iron accumulation (NBIA). NBIAs are a group of rare inherited disorders characterized by iron accumulation in the brain. Aceruloplasminemia is also classified as an iron overload disorder.

Treatment is directed toward the specific symptoms and may include iron chelator medications.

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Synonyms

• familial apoceruloplasmin deficiency
• hereditary ceruloplasmin deficiency

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Signs & Symptoms

The symptoms and severity of aceruloplasminemia vary from one person to another, even among members of the same family. The age of onset varies as well, ranging from anywhere between the 20s and 60s.

The three main findings associated with aceruloplasminemia are retinal degeneration, neurological symptoms and diabetes mellitus.

• Retinal degeneration: Many affected individuals develop progressive degeneration of the retinas.
  • The retinas are the thin layers of nerve cells that line the inner surface of the eyes. They are responsible for sensing and converting light into nerve signals which are then relayed to the brain through the optic nerve.
  • The damage to the retinal tissue can be caused by iron buildup or be related to diabetes that develops as part of aceruloplasminemia.
• Neurological symptoms: Neurological symptoms are due to the buildup of iron in the brain and may include:

• • Behavioral changes including depression

• • Cognitive impairment which can progress to dementia

• Diabetes mellitus: Due to iron accumulation and damage to the pancreas, diabetes mellitus may occur.
  • The pancreas is a small organ located behind the stomach that secretes digestive enzymes and hormones such as insulin which helps break down sugar.
    • Diabetes is a common disorder in which the body does not produce enough or is unable to properly use insulin. The main symptoms are unusually excessive thirst and urination.

Other common features include:

• Anemia: Affected people may also have mild anemia (low levels of circulating red blood cells) which can cause fatigue, weakness, shortness of breath and pale skin.
  • Anemia often occurs before the development of other symptoms commonly associated with aceruloplasminemia.
• Heart failure: Iron accumulation in the heart can result in heart failure.
• Hypothyroidism: Iron accumulation in the thyroid can result in an underactive thyroid.

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Causes

Aceruloplasminemia is caused by changes (disease-causing variants) in the ceruloplasmin (CP) gene. The CP gene contains instructions for producing the enzyme ceruloplasmin. This enzyme is essential for the proper function and transport of iron within the body. Variants of the CP gene cause low levels of functional ceruloplasmin, which ultimately results in the accumulation of iron in the brain and other organs of the body. Iron accumulation damages the tissue of affected organs causing the characteristic symptoms of aceruloplasminemia.

Iron is a critical mineral that is found in all cells of the body and is essential for the body to function and grow properly. Iron is found in many types of food including red meat, poultry, eggs and vegetables. Iron levels must remain within a specific range in the body, otherwise anemia (due to low iron levels) will occur, or damage to affected organs (due to high iron levels) will occur.

In most individuals with aceruloplasminemia, iron accumulates within the basal ganglia, a part of the brain that processes information involved in involuntary movements, coordination and cognition. The specific neurological symptoms that develop in aceruloplasminemia depend on the exact location and amount of iron accumulation within the brain.

Diabetes associated with aceruloplasminemia is caused by iron accumulation in the pancreas. Iron can also accumulate elsewhere in the body such as the retinas or liver. However, liver damage does not usually occur in aceruloplasminemia.

Aceruloplasminemia is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

In most recessive conditions, individuals with one normal gene and one gene for the disease (carriers) do not develop symptoms; however, aceruloplasminemia carriers may, in rare cases, develop problems coordinating movements (cerebellar ataxia).

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Affected populations

Aceruloplasminemia is an extremely rare disorder that affects males and females in equal numbers. The exact incidence of aceruloplasminemia is unknown. It may be more common in Japan, where it is estimated to affect 1 individual per 2,000,000 in the general population. Because many cases of aceruloplasminemia go undiagnosed or misdiagnosed, determining the true frequency in the general population is difficult. Aceruloplasminemia was first described in medical literature in 1992.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of aceruloplasminemia. Comparisons may be useful for a differential diagnosis.

Neurodegeneration with brain iron accumulation (NBIA) is a general term for a rare group of genetic disorders characterized by the accumulation of iron in the brain. NBIAs include:

• pantothenate kinase associated neurodegeneration (formerly Hallervorden-Spatz disease)
• PLA2G6-Associated Neurodegeneration (Seitelberger disease)
• neuroferritinopathy
• Wilson disease

Iron overload disorders are a group of disorders characterized by the accumulation of iron in the body, especially in internal organs such as the liver and heart. Aceruloplasminemia is considered a type of iron overload disorder, although, in the other disorders in this group, the brain is not usually affected. These disorders include:

• hemochromatosis
• neonatal hemochromatosis
• astransferrinemia
• African iron overload disease

A variety of neurological disorders have symptoms that are similar to aceruloplasminemia including:

• Parkinson’s disease
• dystonia
• hereditary ataxias
• Huntington’s disease
• multiple system atrophy
• dentatorubral-pallidoluysian atrophy

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Diagnosis

A diagnosis of aceruloplasminemia is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood tests can reveal certain findings associated with aceruloplasminemia including absent blood ceruloplasmin and low concentrations of copper and iron in serum. Magnetic resonance imaging (MRI) of the brain and liver can reveal characteristic findings that indicate the accumulation of iron. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. A genetic test to find disease-causing variants in the CP gene is the definitive diagnostic test.

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Standard Therapies

Treatment
The management of aceruloplasminemia focuses on improving the specific symptoms that the affected person has. Currently used treatment options involve:

• Iron chelation therapy: Iron chelators such as deferiprone and deferoxamine are used to reduce systemic iron overload.
  • An iron chelator is a substance that binds to excess iron in the body. This makes it dissolvable in water, allowing it to be excreted through the kidneys.
  • Deferiprone can cross the blood-brain barrier which may decrease brain iron accumulation.
    • However, it is not known if it can stop the neurological progression of disease, especially in advanced disease stages and it remains unclear whether iron chelation significantly improves symptoms in aceruloplasminemia.
• The combination of deferiprone with periodic blood removal (phlebotomy) has shown effectiveness in reducing systemic iron levels but it may result in anemia.
  • Research indicates that early intervention may help delay neurological progression of disease.
• Antioxidants: Antioxidants like vitamin E and zinc sulfate may prevent tissue damage by reducing oxidative stress caused by unstable molecules called free radicals.
  • Antioxidants can be used alone or in combination with an iron chelator or oral zinc sulfate.

Some people affected by aceruloplasminemia have been treated with fresh frozen plasma to restore normal ceruloplasmin levels. When combined with deferoxamine, this approach has led to a reduction in iron levels in the liver. In some people, repeated transfusions of fresh frozen plasma have also decreased iron levels in the brain.

Some studies have shown that ceruloplasmin given in the vein (parenteral ceruloplamin) may restore iron metabolism and reduce oxidative stress. While this could be a future treatment option as it targets the cause of the condition, it is not yet widely available for clinical use.

Other treatments aim to manage symptoms and provide support. This includes careful management of diabetes through diet, oral medications, or insulin injections, as required.

Genetic counseling is recommended for affected individuals and their families to provide guidance on the condition and its inheritance.

People with aceruloplasminemia are advised to avoid substances that can increase iron levels in the body.

Research is ongoing with innovative approaches, such as gene therapy to correct the genetic defect underlying aceruloplasminemia.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact: www.centerwatch.com

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Rimoin D, Connor JM, Pyeritz RP, Korf BR. Eds. Emory and Rimoin’s Principles and Practice of Medical Genetics. 4th ed. Churchill Livingstone. New York, NY; 2002:2657.

Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:3147.

JOURNAL ARTICLES
Romano N, Baiardi G, Pinto VM, et al. Long-Term Neuroradiological and Clinical Evaluation of NBIA Patients Treated with a Deferiprone Based Iron-Chelation Therapy. J Clin Med. 2022;11(15):4524. Published 2022 Aug 3. doi:10.3390/jcm11154524

Zanardi A, Nardini I, Raia S, et al. New orphan disease therapies from the proteome of industrial plasma processing waste- a treatment for aceruloplasminemia. Commun Biol. 2024;7(1):140. Published 2024 Jan 30. doi:10.1038/s42003-024-05820-7

McNeill A, Pandolfo M, Kuhn J, Shang H, Miyajima H. The neurological presentation of ceruloplasmin gene mutations. Eur Neurol. 2008;60(4):200-205. doi:10.1159/000148691

Kuhn J, Bewermeyer H, Miyajima H, Takahashi Y, Kuhn KF, Hoogenraad TU. Treatment of symptomatic heterozygous aceruloplasminemia with oral zinc sulphate. Brain Dev. 2007;29(7):450-453. doi:10.1016/j.braindev.2007.01.001

Mariani R, Arosio C, Pelucchi S, et al. Iron chelation therapy in aceruloplasminaemia: study of a patient with a novel missense mutation. Gut. 2004;53(5):756-758. doi:10.1136/gut.2003.030429

Miyajima H. Aceruloplasminemia, an iron metabolic disorder. Neuropathology. 2003;23(4):345-350. doi:10.1046/j.1440-1789.2003.00521.x

Gitlin JD. Aceruloplasminemia. Pediatr Res. 1998;44(3):271-276. doi:10.1203/00006450-199809000-00001

Harris ZL, Klomp LW, Gitlin JD. Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis. Am J Clin Nutr. 1998;67(5 Suppl):972S-977S. doi:10.1093/ajcn/67.5.972S

Morita H, Inoue A, Yanagisawa N. Rinsho Shinkeigaku. 1992;32(5):483-487.

INTERNET
Miyajima H, Hosoi Y. Aceruloplasminemia. 2003 Aug 12 [Updated 2018 Sep 27]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1493/ Accessed January 15, 2025.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:604290; Last Update:03/05/2024. Available at: https://omim.org/entry/604290 Accessed January 15, 2025.

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