An ultra-rare form of NBIA known as CoPAN, or COASY Protein-Associated Neurodegeneration, is caused by a mutation in the COASY (Coenzyme A Synthase) gene on chromosome 17. CoPAN is so rare that only a few cases have been identified in the world.
Onset typically occurs in childhood, presenting first with spasticity and dystonia of the lower limbs and later with dystonia of the mouth and jaw. Speech problems also occur, including stuttering and slurring words caused by dysarthria (weakened muscles needed for speaking).
CoPAN can be diagnosed through an MRI (T2-weighted) scan of the brain.
Based on one individual’s scan, the MRI showed hypointensity, or a darkened area that can indicate iron deposits, in the brain’s substantia nigra and globus pallidus. In another case, the scan showed hyperintensity (white spots that highlight problematic regions) and swelling in the brain’s caudate nuclei, putamina and thalamus. A third individual’s scan showed calcifications in the globus pallidus.
The diagnosis of CoPAN can be confirmed through genetic testing of the COASY gene to identify mutations.
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with CoPAN, the following evaluations may be useful:
- A neurologic examination for dystonia, rigidity, spasticity and parkinsonism, including a formal evaluation for walking (ambulation) and speech.
- An informal developmental assessment, with a referral for more formal testing if a delay is indicated.
- An assessment for physical therapy, occupational therapy, and/or speech therapy, as well as appropriate assistive devices.
- A psychiatric assessment for possible obsessive-compulsive behavior.
While there is no standard treatment for CoPAN, symptom management is available. Most are aimed at dystonia, which can be debilitating. Management tactics used with varying degrees of success include:
- Oral medications: baclofen, anticholinergics, tizanidine and dantrolene
- Botox: focal injections of botulinum toxin into muscles affected by dystonia. Botox can provide relief for several months from involuntary contractions, twisting, abnormal posture or changes in a person's voice or speech. Because each affected muscle must be injected, this is most practical when an individual has dystonia significantly affecting a specific body area, such as the hand or jaw. Resistance to Botox is a phenomenon, which may cause the treatment to lose its effectiveness over time. This occurs because the body makes antibodies to combat the toxin.
- Intrathecal baclofen therapy: Although baclofen is usually taken orally, a baclofen pump may be an option for some individuals. An evaluation can be done to determine whether a patient would respond positively to a pump, which is surgically implanted under the skin of the abdomen.
- DBS: deep brain stimulation. This involves placing electrodes in the brain and attaching the wires to a battery-operated neurostimulator implanted in the chest. The neurostimulator sends pulses to targeted areas in the brain and takes “offline” the part sending too many signals and causing the muscles to move in painful ways. DBS is the most commonly performed surgical treatment for Parkinson's disease.
The symptoms of parkinsonism in NBIA individuals can be treated with the same medications used in Parkinson’s disease.
More information on these therapies can be found in the Medical Information section of our website.
Notice if the individual has problems swallowing to prevent aspiration. Additionally, pay attention to diet and regularly measure height and weight in children to assure adequate nutrition. A gastrostomy tube can be placed if needed. Clinicians also recommend assessing ambulation and speech and communication needs. While the symptoms of CoPAN typically progress slowly, individuals in their 30s often have lost their ability to walk and must use a wheelchair.
CoPAN is inherited in an autosomal recessive manner. Because most of our genes exist in pairs (one from the mother, one from the father), we normally carry two working copies of each gene. When a person has one copy of a recessive gene with a change (mutation) in it, the individual is not affected by the disease. That person is called a carrier.
Recessive diseases only occur when both parents are carriers for the same diseaseand pass their mutated genes onto their child. Statistically, there is a one in four chance that two carriers would have an affected child. The chance is two in four that two carriers would have a child who is also a carrier, and it’s one in four that the child will not have the mutation. Carrier testing for relatives and prenatal testing for at-risk pregnancies are suggested if both disease-causing mutations have been identified in an affected family member.
When the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies can be done. In one test, DNA is extracted from fetal cells obtained by amniocentesis, usually at 15 to 18 weeks of gestation.
Alternatively, the chorionic villus, the tiny finger-like projections on the edge of the placenta, are tested, usually at 10 to 12 weeks gestation. Embryo screening, known as preimplantation genetic diagnosis, may be an option for some families.
Natural History Studies
Researchers conduct natural history studies to understand changes in disease-affected individuals over time. 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.
The recessive mutations in CoA Synthase (COASY) that cause COPAN were first uncovered in 2013 by Sabrina Dusi of The Firc Institute of Molecular Oncology, a research center in Milan, Italy. This study used exome sequencing for individuals who had an NBIA clinical presentation and neuroimaging indications but lacked the mutations in previously discovered genes. It resulted in this publication:Exome Sequence Reveals Mutations in CoA Synthase as a Cause of Neurodegeneration with Brain Iron Accumulation
Coenzyme A (CoA) is important to all living organisms because of its involvement in numerous enzymatic reactions. It is a key molecule for metabolizing fatty acids, carbohydrates, amino acids and ketone bodies. The last two steps of its biosynthesis are carried out by CoA Synthase, where the COPAN mutation occurs. Normal Coenzyme A Synthase is crucial for healthy nervous system function.
Because CoPAN is so rare, more studies are needed to better understand it.