ACERULOPLASMINEMIA

The mutations in the gene named CP producing Ceruloplasmin are responsible for Aceruloplasminemia which is a form of NBIA characterized by iron accumulation characterized by iron accumulation in both the brain and visceral (internal) organs.

The disorder has mainly been studied in Japan, where it occurs in about one in 2 million adults. It is unclear how often it occurs in other populations.

Age at onset is 25 to 60, and older. Psychiatric problems in patients include depression and cognitive dysfunction in individuals older than age 50. The average lifespan varies for individuals with aceruloplasminemia, but due to improvements in medical care, more affected individuals are now living well into late adulthood.

The main symptoms are retinal degeneration, diabetes and neurologic disease related to iron build-up in the basal ganglia. Movement problems include face and neck dystonia (involuntary muscle contractions, with repetitive movements or painful postures), blepharospasm (eyelid spasms), tremors and jerky movements.

Clinical Diagnosis

Individuals with aceruloplasminemia often present to doctors with anemia (age 15) prior to onset of diabetes mellitus or neurologic symptoms. Physical traits, known as phenotypic expression, vary, even within families.

One of the main indications of an aceruloplasminemia diagnosis is evidence of iron accumulation in both the brain and some internal organs. Therefore, in order to correctly diagnose aceruloplasminemia, both brain and abdominal MRIs are necessary. The MRI will show signs of iron accumulation in the brain (striatum, thalamus, dentate nucleus) and liver on both T1- and T2-weighted images.

The laboratory tests also will indicate the absence of serum ceruloplasmin, a copper-containing protein, and some combination of the following: low serum copper concentration, low serum iron concentration, high serum ferritin (a protein that enables cells to store iron) concentration, and increased iron concentration in the liver.

In most individuals, the three major symptoms (retinal degeneration, diabetes mellitus, and neurologic disease) first appear in adulthood.

Retinal degeneration was found in 93 percent of Japanese individuals with aceruloplasminemia [Miyajima, et. al., 2003]. Visual acuity is not affected.

SYMPTOMS

Individuals from age 25 to older than age 60 start to develop the symptoms of aceruloplasminemia.

Common symptoms

Retinal degeneration (deterioration of the retina in the back of the eye)

Diabetes causes individuals to have high blood sugar. It can result in symptoms such as frequent urination, increased thirst and increased hunger. Diabetes is caused by iron accumulation and damage in the pancreas, where insulin is made

Ataxia (uncoordinated, jerky movement of the muscles).

Involuntary movement

Parkinsonism (symptoms similar to Parkinson’s disease) tremors (shaking), hypokinesia (decreased muscle movement), rigidity (stiffness). akinesia (cannot initiate muscle movement―cannot get started)

Cognitive (mental) decline, Generally seen in individuals older than age 50. It can lead to dementia

Anemia a decrease in the number of red blood cells or a decrease in the quantity of hemoglobin in the blood. Individuals may show anemia before a diagnosis of diabetes or neurologic problems.

Psychiatric problems depression

DIAGNOSIS & TESTING

The diagnosis of aceruloplasminemia is made through a combination of laboratory findings, a brain and an abdominal MRI.

Laboratory tests

Brain and abdominal MRI

Rarely, an individual with the signs and symptoms of aceruloplasminemia may have only one or no CP gene changes identified. This can happen because the genetic testing is not perfect and has certain limitations. It does not mean the person does not have aceruloplasminemia; it may just mean we do not yet have the technology to find the hidden gene changes. In these cases it becomes very important to have doctors experienced with aceruloplasminemia review the MRI and the person’s symptoms carefully to be as sure as possible of the diagnosis.

Management

There is no standard treatment for aceruloplasminemia. A team of medical professionals recommends treatments based on current symptoms. Chelation therapy should be considered since iron accumulates in both the brain and the body organs.

Evaluations of disease progression

To establish the extent of disease

The high levels of iron in individuals with aceruloplasminemia can be treated using a variety of therapies and medications including: Iron chelating agents, such as desferrioxamine (intravenous) and deferasiox (oral medication) are sometimes used to decrease serum ferritin concentration, decrease brain and liver iron stores, and prevent progression of neurologic signs and symptoms in symptomatic individuals with blood hemoglobin concentration higher than 9 grams per deciliter.

Long-term surveillance for aceruloplasminemia

The symptoms of parkinsonism can be treated with the same medications used in Parkinson’s disease. Treatment with dopamine agonist drugs (like levodopa) must be started and monitored carefully. In the beginning, the dose is increased gradually until both the patient and doctor feel symptoms are under control. While taking dopaminergic drugs, individuals must be regularly monitored for adverse neuropsychiatric effects, psychiatric symptoms and worsening of parkinsonism. The benefits of the medication usually only last a few years and are eventually limited by the development of disabling dyskinesias (difficulty performing voluntary movements).

Even after a diagnosis has been made and the appropriate therapies have been decided, it is recommended to continue long-term surveillance to decrease the impact of aceruloplasminemia symptoms and increase quality of life.

Causes

The CP gene that is altered in those with aceruloplasminemia and inherited in an autosomal recessive manner. “Autosomal” refers to the fact that the CP gene is located on chromosome 3, which is one of the autosomes. “Recessive” refers to the fact that a gene change must be present in both copies of the CP gene for a person to have aceruloplasminemia.

The mutations in CP gene are known to cause aceruloplasminemia. The gene CP codes for a protein called ceruloplasmin, which carries copper in the blood and plays a role in iron metabolism (breakdown).

An individual having only one CP gene change are called a “carrier” for . Carriers do not have health problems related to the gene change and often do not know they carry a recessive gene change. Two carriers having a child together, then there is a 25% chance that they will both pass on their recessive CP gene changes and have a child with of the child having aceruloplasminemia and a 50% chance that the child will be a carrier like his/her parents and a 25% chance that the child will not have aceruloplasminemia or be a carrier.

Carrier testing for at-risk relatives and prenatal testing for pregnancies at risk are possible if both disease-causing mutations have been identified in an affected family member.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells through amniocentesis (usually at 15 to 18 weeks’ gestation) or sampling of the chorionic villus – the finger-like projections that emerge from the outer sac surrounding the fetus – (usually at 10 to 12 weeks’ gestation).

Screening embroyos before they become implanted may be an option for some families in which the disease-causing mutations have been identified.

 

Please see the link in the right hand column on this page for more detailed information on aceruloplasminemia at Gene Reviews, which was used as a source for some of the above information.

Gene Reviews Author:

Hiroaki Miyajima, MD

First Department of Medicine

Hamamatsu University School of Medicine

Hamamatsu, Japan

miyajima@hama-med.ac.jp