Aceruloplasminemia
Aceruloplasminemia was first described in 1987 as an autosomal recessive disease, meaning that an affected individual has inherited the defective gene from both parents. The disorder is caused by a mutation of the ceruloplasmin gene (CP), which is inactivated. The estimated prevalence of this disease is about one in 2 million. It has been mainly studied in Japan, where it is most prevalent.
While other NBIA disorders cause iron accumulation in the brain, aceruloplasminemia is unique in that it causes iron overload not only in the brain but also in other organs such as the liver, pancreas and heart.
The main symptoms are retinal degeneration, diabetes and neurologic disease related to iron build-up in the brain’s 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 before the onset of diabetes mellitus or neurologic symptoms. Physical traits, known as phenotypic expression, vary, even within families.
The classical disease triad of aceruloplasminemia is diabetes, retinopathy and neuropathy. Diabetes mellitus is considered an early sign. It was reported as the first symptom in 68.5% of patients at a median age of 38.5 years (Vroegindeweij et al., 2015). Retinal symptoms are reported in over 75% of Japanese patients (Kono, 2012). These retinal manifestations do not affect visual acuity.
Neurological symptoms usually appear in the fifth decade of life and vary within a wide spectrum that includes cerebellar ataxia (sudden, uncoordinated muscle movement), involuntary movements, parkinsonism (movement disorder), mood and behavior disturbances, and cognitive impairment.
Physicians may do an MRI to assist in diagnosing patients. 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 images 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. Laboratory blood tests can also test these concentrations.
Age at onset is 25 to 60, and older. Psychiatric problems in patients include depression and cognitive dysfunction in individuals older than 50.
When phenotypic and laboratory findings suggest the diagnosis of aceruloplasminemia, molecular genetic testing can include single gene testing, multigene panels or comprehensive genomic testing.
Evaluations Following Initial Diagnosis
To establish the extent of disease and the individual’s needs, evaluations for the following are recommended:
- Iron deposits. Serum ferritin concentration, brain and abdomen MRI findings, and hepatic (liver) iron and copper content by liver biopsy
- Neurologic findings. Brain MRI and protein concentration in cerebrospinal fluid
- Diabetes mellitus. Blood concentrations of insulin and HbA1c, a test of blood sugar levels
- 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
- Anemia. Complete blood count
- Medical genetics consultation
Annual glucose tolerance tests starting at age 15 are recommended to evaluate the onset of diabetes mellitus. A cardiac evaluation should be performed early in the course of the disease and repeated every year. Finally, evaluation of thyroid and liver function and complete blood count are indicated annually starting at the time of diagnosis.
Management
Treatment is focused on reducing iron overload using iron chelating agents, such as desferrioxamine, deferasirox and deferiprone. While iron chelation therapy (ICT) was effective in reducing systemic iron overload, it was not effective on neurological symptoms [Kono 2013; Dusek et al., 2016]. It also must often be discontinued due to iron deficiency anemia.
More research needs to be done on the therapeutic efficacy of ICT in aceruloplasminemia. There is no information on whether it can improve glucose metabolism and retinopathy, and only short-term studies have been done on the effect on neurological symptoms. It is possible that the treatment would be more effective if started in the window between the appearance of the first signs of disease and the neurological symptoms. Zinc sulfate and minocycline have been proposed as alternatives to ICT due to their antioxidant properties. The results are promising but are limited to only two patients [Kuhn et al. 2007; Hayashida et al., 2016].
In some cases, ICT was combined with fresh-frozen plasma (FFP) administration. FFP can partially/temporarily restore circulating ceruloplasmin (Cp). A 2017 case report suggests that the early initiation of combined treatment with FFP and iron chelation may be useful to reduce the accumulation of iron in the central nervous system and improve neurological symptoms.
Genetics
Aceruloplasminemia is inherited in an autosomal recessive manner. Because most of our genes exist in pairs (one coming from the mother and one coming from the father), we normally carry two working copies of each gene. When one copy of a recessive gene has a change or mutation, the person should still have normal health. That person is called a carrier.
Recessive diseases only occur when both parents are carriers for the same condition and then pass their changed genes onto their child. Statistically, there is a one in four chance that two carriers would have an affected child. The chance is one in four that their child will not 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 embryos before they become implanted may be an option for some families in which the disease-causing mutations have been identified.
Note
A main resource for this clinical information is Aceruloplasminemia - GeneReviews - NCBI Bookshelf. GeneReviews is primarily for the use of genetics professionals so the terminology and information may be difficult to understand for the general public.
TIRCON International NBIA Registry
The TIRCON International NBIA Registry is housed at Ludwig Maximilian University of Munich, Germany, and was created under an EU grant from 2011-2015 called Treat Iron-Related Childhood-Onset Neurodegeneration.
The NBIA Alliance and other sources have provided registry funding since 2015. Clinical centers from 16 countries have provided patient clinical data. There are over 750 entries consisting of NBIA patients and controls as of September 2021. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data are available to researchers studying NBIA disorders. Contact Anna Baur-Ulatowska at Anna.Baur@med.uni-muenchen.de for more information on this registry.
Clinical Trials
Clinical trial information can be found at ClinicalTrials.gov by searching for aceruloplasminemia. Currently, one study is in the recruitment process at First Affiliated Hospital of Fujian Medical University. More information can be found at Clinical Curative Effect Evaluation Study of Treatment of Oral Deferiprone Tablets in Aceruloplasminemia.
Aceruloplasminemia Research Publications and Articles
Following is a list of recent aceruloplasminemia research articles. Other research articles and studies can be found at Pub Med Central.
2019 - Aceruloplasminemia: A Severe Neurodegenerative Disorder Deserving an Early Diagnosis
2018 - Aceruloplasminemia: Waiting for an Efficient Therapy
2017 - Is aceruloplasminemia treatable? Combining iron chelation and fresh-frozen plasma treatment
2016 - Iron chelation in the treatment of neurodegenerative diseases
2015 - Aceruloplasminemia presents as Type 1 diabetes in non‐obese adults: a detailed case series
2013 - Aceruloplasminemia: an update
2007 - Treatment of symptomatic heterozygous aceruloplasminemia with oral zinc sulphate
2006 - Molecular and pathological basis of aceruloplasminemia
Cited on Page
Dusek P., Schneider S. A., Aaseth J. (2016). Iron chelation in the treatment of neurodegenerative diseases. J. Trace Elem. Med. Biol. 38 81–92. 10.1016/j.jtemb.2016.03.010 [PubMed]
Hayashida M., Hashioka S., Miki H., Nagahama M., Wake R., Miyaoka T., et al. (2016). Aceruloplasminemia with psychomotor excitement and neurological sign was improved by minocycline (case report). Medicine 95:e3594. 10.1097/MD.0000000000003594 [PubMed]
Kuhn J., Bewermeyer H., Miyajima H., Takahashi Y., Kuhn K. F., Hoogenraad T. U. (2007). Treatment of symptomatic heterozygous aceruloplasminemia with oral zinc sulphate. Brain Dev. 29 450–453. 10.1016/j.braindev.2007.01.001 [PubMed]
Kono S. (2012). Aceruloplasminemia. Curr. Drug Targets 13 1190–1199. 10.2174/138945012802002320 [PubMed]
Kono S. (2013). Aceruloplasminemia: an update. Int. Rev. Neurobiol. 110 125–151. 10.1016/B978-0-12-410502-7.00007-7 [PubMed]
Vroegindeweij L. H., Van Der Beek E. H., Boon A. J., Hoogendoorn M., Kievit J. A., Wilson J. H., et al. (2015). Aceruloplasminemia presents as Type 1 diabetes in non-obese adults: a detailed case series. Diabet. Med. 32 993–1000. 10.1111/dme.12712 [PubMed]
