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.
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.
Individuals from age 25 to older than age 60 start to develop the symptoms of aceruloplasminemia.
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).
- Gait ataxia (jerky, unsteady walking).
- Limb ataxia (jerky, unsteady movement).
- Dysarthria is the difficulty using or controlling the muscles of the mouth, tongue, larynx or vocal cords which are used to make speech. This can make a person’s speech difficult to understand in several different ways, including stuttering, slurring, or soft or raspy speech.
- Nystagmus (repetitive, uncontrolled back-and-forth eye movements). It can result in reduced vision, sometimes called “dancing eyes”
- Dystonia (involuntarily muscle contraction and spasms) Face and neck
- Blepharospasm (sustained, forced, involuntary closing of the eyelids)
- Chorea (brief, irregular muscle movements that occur involuntarily and cannot be controlled by the person experiencing them)
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.
- Absence of serum ceruloplasmin (a protein that carries and transports copper)
- Low serum copper and iron concentration
- High concentration of serum ferritin (a protein that carries and transports iron)
- Increased iron concentration in the liver
Brain and abdominal MRI
- Hypointensity (darkness) in the globus pallidus, striatum, thalamus, and dentate nucleus on T2 MRI. The dark patches indicate iron accumulation
- Cerebellar atrophy (decrease in cerebellum size)
- Iron accumulation in the visceral organs, especially the liver, pancreas and heart. Iron concentration in the liver is greater than in the brain
- Genetic testing to find the change in two copies of CP gene. Genetic testing is done through sequence analysis, which is able to find the gene change in >92% of cases.
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.
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
- Iron deposits serum ferritin concentration, brain and abdomen MRI findings, and hepatic (liver) iron and copper content by liver biopsy
- Diabetes mellitus. Blood concentrations of insulin and HbA1c, a test of blood sugar levels.
- Neurological examination brain and abdomen MRI and protein concentration in cerebral spinal fluid.
- Eye exams retinal degeneration. Examination of the optic fundi, the interior linking of the eyeball, and fluorescein angiography, a test to examine blood vessels in the retina, choroid and iris of the eye.
- Medical genetics consultation
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.
- Desferrioxamine intravenous used in individuals with blood hemoglobin concentration higher than 9 g/dL. Decreases the concentration of iron in the brain, liver and other visceral organs. Decreases serum ferritin concentration. Slows the progression of neurologic symptoms.
- Deferasiox (oral medication) mildly improves cognitive performance, gait and balance. may be used in individuals who do not respond to desferrioxamine or fresh-frozen plasma therapy (FFP)
- Combination of IV desferrioxamine and fresh-frozen human plasma (FFP). FFP contains ceruloplasmin. Repeat FFP treatments can improve neurologic symptoms and reduce iron in the liver. The combination of FFP and desferrioxamine is more effective than FFP alone
- Antioxidants (such as vitamin E) used along with a chelator or oral administration of zinc prevents tissue damage, particularly to the liver and pancreas
Long-term surveillance for aceruloplasminemia
- Regular eye exams to monitor for retinal degeneration
- Annual glucose tolerance test to check for signs of diabetes started at age 15 or as soon as diagnosis is made
- ECG (electrocardiogram) evaluation Is done early in the course of the disease and used to look for signs of cardiac failure from iron accumulation in the heart muscle
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.
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.
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