NORD gratefully acknowledges Alisdair McNeill PhD MRCP (UK) DCH, Senior Clinical Fellow & Honorary Consultant, Sheffield Institute for Translational Neuroscience, for assistance in the preparation of this report.
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 as an autosomal recessive trait.
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.
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.
Aceruloplasminemia is caused by mutations of the ceruloplasmin (CP) gene. It is inherited as an autosomal recessive trait. 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 the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one 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 defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. 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, in aceruloplasminemia carriers may, in rare cases develop cerebellar ataxia (problems coordinating movements).
Investigators have determined that the CP gene is located on the long arm (q) of chromosome 3 (3q23-q24). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 3q23-q24” refers to bands 23-24 on the long arm of chromosome 3. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
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.
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. More than 32 cases of aceruloplasminemia have been reported in the medical literature as of 2008. Aceruloplasminemia was first described in the medical literature in 1992.
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.
The treatment of aceruloplasminemia is directed toward the specific symptoms that are apparent in each individual. Individuals with aceruloplasminemia may be treated with a drug called desferrioxamine, an iron chelator. Iron chelators are drugs that bind to the excess iron in the body allowing it to be dissolved in water and excreted from the body through the kidneys. Desferrioxamine has decreased iron in the brain and liver and prevented the progression of neurological symptoms in symptomatic individuals with blood iron levels greater than 9 grams per deciliter (g/dL).
Individuals with aceruloplasminemia should avoid substances that increase the levels of iron in the body.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. Of particular importance is management of diabetes, with appropriate diet, tablets and insulin injects as needed.
Individuals with aceruloplasminemia have also been treated with fresh frozen plasma to restore normal levels of functional ceruloplasmin. Individuals treated with fresh frozen plasma and desferrioxamine have experienced a decrease in the levels of iron in the liver. Repeated transfusions of fresh frozen plasma have led to a decrease in levels of iron in the brain in some cases.
Antioxidants such as vitamin E have been used along with an iron chelator or with oral zinc sulfate to prevent tissue damage in individuals with aceruloplasminemia. Antioxidants are substances that are believed to protect cells from damage from unstable molecules called free radicals.
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