CoPAN

CoPAN, or COASY Protein-Associated Neurodegeneration is caused by a mutation in the COASY gene which codes for a protein named Coenzyme-A Synthase. CoPAN is an NBIA disorder that is characterized by spaticity and weakness of the lower limbs early in the disease and iron accumulation and calcifications found in the globus pallidus.

SYMPTOMS

At this time only a few cases have been identified with this rare form of NBIA. There are only a few cases of CoPAN that have been reported, so information about CoPAN may change once more affected individuals are identified.

At present, the symptoms of CoPAN start to appear in childhood and spasticity and dystonia of the lower limbs are present early on, while dystonia of the mouth and jaw appears later in the disease process. Speech problems are also seen, including stuttering and slurry of words, caused by dysarthria.

Common symptoms

Spastic-dystonic paraparesi develops early in the disease

• Lower limbs spasticity (stiff or rigid muscles), dystonia (involuntary muscle contraction and spasms), and weakness

Oro-mandibular dystonia develops later in the disease

• Involuntarily muscle contraction and spasms of the mouth, jaw and tongue

Dysarthria (speech problems)

• 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

Axonal neuropathy

• Nerve cells begin to function abnormally because the axons (which send signals from one nerve cell to another) are deteriorating

Parkinsonism (symptoms similar to Parkinson’s disease)

• Bradykinesia (slow movement)
• Rigidity (stiffness)
• Tremors (shaking)

Cognitive impairment

• More research is needed to determine the level of impairment

Obsessive-compulsive behavior

CAUSE

CoPAN is inherited in an autosomal recessive manner. Autosomal” refers to the fact that the COASY gene is located on chromosome 17, which is one of the autosomes (chromosome pairs 1-22). Recessive” refers to the fact that a mutation must be present in both copies of the COASY gene for a person to have CoPAN. If an individual has only one COASY mutation, then they are called a “carrier” for CoPAN. Carriers do not have health problems related to the mutation and often do not know they carry a recessive gene mutation. However, if two CoPAN carriers have a child together, then there is a 25% chance that they will both pass on their recessive COASY gene mutations and have a child with CoPAN. There is a 25% chance of the child having CoPAN and a 50% chance that the child will be a carrier like his/her parents. There is a 25% of the child being no carrier of this mutation.

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

Diagnosis

• hypointensity, the dark patches on T2-weighted MRI views of the brain in the substantia nigra and the globus pallidus were found in one case. indicate iron accumulation.
• hyperintensity, the bright patches on T2-weighted MRI views of the brain and swelling in the caudate nuclei, putamina and thalamus in another individual.
• Calcifications in the globus pallidus in one individual. Appear as a central region of hyperinternsity (brightness) in the middle of a dark patch of iron accumulation in the globus pallidus and resemble the eye-of-the-tiger sign seen in the PKAN type of NBIA. However, additional testing using an axial CT showed that the bright areas were calcifications.

Diagnosis of CoPAN can be confirmed through genetic testing of the COASY gene to find gene changes. Genetic testing is done through sequence analysis.

CoPan Evaluations

To establish the extent of disease in an individual diagnosed with CoPAN, the following evaluations may be useful:

• Neurologic examination for dystonia, rigidity, spasticity and parkinsonism, including formal evaluation of ambulation and speech.
• Screening for developmental assessment, with referral for more formal testing if delay is indicated
• Assessment for physical therapy, occupational therapy, and/or speech therapy and appropriate assistive devices
• Psychiatric assessment for possible obsessive-compulsive behavior.
• Medical genetics consultation

Management

There is no standard treatment for CoPan and treatments are based on managing symptoms by a team of medical professionals. Individuals with CoPAN are recommended to get the following:

Therapies to manage dystonia

• Intramuscular botulinum toxin, Botox is injected in spastic, dystonic muscles to help them relax for a period of time
• Anticholinergics, tizanidine, and dantrolene
• Artane (trihexyphenidyl) Taken orally, usually divided into multiple doses each day
• Baclofen (oral or intrathecal) One of the main drugs used to treat dystonia, usually first taken orally and divided into several doses each day. In the intrathecal method, an implanted baclofen pump delivers medication directly into the spinal fluid
• Deep brain stimulation Used increasingly more often in NBIA and has some evidence for benefit. A stimulator sends electrical impulses to the affected brain region to help muscles relax. It involves surgical implantation of a lead, extension and battery pack (IPG). The lead contains 4 electrodes and is implanted in the globus pallidus region of the brain. The extension connects the lead to the battery pack (IPG). The IPG is a battery-powered neurostimulator that is placed in the abdomen (or in some cases below the clavicle)
• Physical and occupational therapy May or may not be indicated for those who are only mildly symptomatic. Therapies to maintain normal joint mobility for as long as possible may be useful
• Parkinsonism The symptoms similar to Parkinson 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. There is often short-term great benefit from Parkinsons medications. However, this usually only lasts a few years and is often eventually limited by the development of dyskinesias (a common side effect that creates unwanted movement).

Long-term surveillance for CoPAN

to decrease the impact of CoPAN symptoms and increase quality of life.

• Medication for spasticity, dystonia, and/or parkinsonism
• Monitoring of individuals receiving dopaminergic drugs for parkinsonism for adverse neuropsychiatric effects, psychiatric symptoms and worsening of parkinsonism
• Nutrition, Monitoring of height and weight in children, swallowing evaluation and regular dietary assessments, assure adequate nutrition, prevent aspiration, Gastrostomy tube placement (as needed)
• Regular assessments of walking and speech abilities

While the symptoms of CoPAN typically progress at a slow rate, by the time most reported individuals with CoPAN reach their 30s, they are no longer ambulatory and are confined to a wheelchair.

PROGRESSION

The symptoms of CoPAN typically progress at a slow rate. However, by the time most reported individuals with CoPAN reach their 30s, the majority can no longer walk. The average lifespan varies for individuals with CoPAN, but due to improvements in medical care, more affected individuals are now living into middle age.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk can be done. In one test, DNA is extracted from fetal cells obtained by amniocentesis, usually at 15 to 18 weeks’ gestation, and analyzed. Or, sampling is done of the chorionic villus, the tiny finger-like projections on the edge of the placenta, usually at 10 to 12 weeks’ gestation.

Embryo screening, known as preimplantation genetic diagnosis, may be an option for some families in which the disease-causing mutations have been identified.