General Discussion

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 mutations of the ceruloplasmin (CP) gene. This mutation is inherited in an autosomal recessive pattern.

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

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.

Some individuals with aceruloplasminemia develop 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.

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. The retinas sense light and convert it to nerve signals, which are then relayed to the brain through the optic nerve. The damage to the retinal tissue can result from iron deposition or be related to the diabetes that develops as part of aceruloplasminemia.

A variety of neurological symptoms occur in individuals with aceruloplasminemia because of the accumulation of iron in the brain. Specific symptoms may vary, but often include movement disorders, an inability to coordinate voluntary movements (ataxia), slurred speech or difficulty speaking (dysarthria), behavioral changes and cognitive impairment.

Movement disorders associated with aceruloplasminemia include tremors, chorea (rapid, involuntary, jerky movements) and dystonia, which refers to a group of muscle disorders generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). An example of dystonia is blepharospasm, a condition characterized by involuntary muscle spasms and contractions of the muscles around the eyes.

Some affected individuals develop symptoms may resemble those found in Parkinson’s disease, which is sometimes referred to as Parkinsonism. These symptoms include tremors, abnormal slowness of movement and an inability to remain in a stable or balanced position. Some individuals with aceruloplasminemia develop cognitive impairment, which can progress to dementia. Behavioral or emotional changes (e.g., depression) may also occur.

Iron accumulation in individuals with aceruloplasminemia may also occur in the pancreas. The pancreas is a small organ located behind the stomach that secretes enzymes that travel to the intestines and aid in digestion. The pancreas also secretes other hormones such as insulin, which helps break down sugar. Damage to the pancreas may ultimately lead to diabetes mellitus. Diabetes is a common disorder in which the body does not produce enough or is unable to properly use insulin. Therefore, the body is not able to properly convert nutrients into the energy necessary for daily activities. The most obvious symptoms are unusually excessive thirst and urination.

Causes

Aceruloplasminemia is caused by mutations of the ceruloplasmin (CP) gene and is inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, 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 non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.

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

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. Mutations of the CP gene result in deficient 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 many types of food including red meat, poultry, eggs and vegetables. Iron levels must remain in a specific range within the body, otherwise they can cause anemia (due to low iron levels) or damage affected organs (due to high iron levels).

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

Diabetes associated with aceruloplasminemia results from iron accumulation in the pancreas. Iron can also accumulate elsewhere in the body such as the retinas or liver. Liver damage does not occur in aceruloplasminemia.

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 prevalent 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 disorder’s true frequency in the general population is difficult. Aceruloplasminemia was first described in the medical literature in 1992.

Related Disorders

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. These disorders may develop during childhood (early-onset, rapid progression) or adulthood (late-onset, slow progression) and iron accumulation most often occurs in the basal ganglia. A variety of neurological symptoms may develop. In addition to aceruloplasminemia, NBIAs include pantothenate kinase associated neurodegeneration (formerly Hallervorden-Spatz disease) and infantile neuroaxonal dystrophy (Seitelberger disease), which are childhood onset recessive conditions, and neuroferritinopathy, which is an autosomal dominant adult onset disorder. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)

Wilson’s disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain, and corneas of the eyes. The disease is progressive and, if left untreated, it may cause liver (hepatic) disease, central nervous system dysfunction, and death. Early diagnosis and treatment may prevent serious long-term disability and life threatening complications. Treatment is aimed at reducing the amount of copper that has accumulated in the body and maintaining normal copper levels thereafter. (For more information on this disorder, choose “Wilson” as your search term in the Rare Disease Database.)

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, and African iron overload disease. (For more information choose the specific disorder name as your search term in the Rare Disease Database.)

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, and dentatorubral-pallidoluysian atrophy. (For more information choose the specific disorder name as your search term in the Rare Disease Database.)

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 particular organs and bodily tissues. A genetic test to demonstrate mutations in the CP gene is the definitive diagnostic test.