NORD gratefully acknowledges Phillip L. Pearl, MD, Chief of Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital, Harvard Medical School, for assistance in the preparation of this report.
The term olivopontocerebellar atrophy (OPCA) has historically been used to describe a group of disorders that affect the central nervous system and are termed neurodegenerative diseases because they result in a progressive deterioration of nerve cells in certain parts of the brain. These conditions are characterized by progressive balance problems (disequilibrium), progressive impairment of the ability to coordinate voluntary movements (cerebellar ataxia), and difficulty speaking or slurred speech (dysarthria).
OPCA has been classified based on clinical, genetic, and neuropathological findings and there is significant controversy and confusion in the medical literature because of its association with two distinct groups of disorders, specifically multiple system atrophy (MSA) and spinocerebellar ataxia (SCA). Hereditary OPCA usually refers to the group of disorders that overlap with SCA. These conditions are discussed in detail in the NORD report on autosomal dominant hereditary ataxias. Sporadic OPCA refers to the group of disorders for which there is not yet evidence of a hereditary component. Some individuals with sporadic OPCA will develop MSA and this disorder is discussed in detail in the NORD report on MSA. In addition, there are rare types of OPCA that follow autosomal recessive inheritance including Fickler-Winkler type OPCA and the pontocerebellar hypoplasia conditions. One type of SCA follows X-linked inheritance. Currently, neurologists usually use the term OPCA as a preliminary diagnosis until a more specific diagnosis can be made with genetic testing or by ruling out other conditions.
Among the different classifications, there is wide variation in severity and age of onset. The symptoms of OPCA differ from person to person. Most patients experience difficulty with balance and coordination of the legs and arms (ataxia) and slurred speech (dysarthria). Other symptoms may include muscle spasms or weakness and stiffness of the muscles; numbness or tingling of the hands or feet; shaking (tremor) of the hand or arm; reduction or slowness of movements; loss of thinking and/or memory skills; difficulty controlling the bladder or bowels; and feeling faint when standing up. Some patients also have fatigue and/or trouble with sleep. Generally, symptoms of OPCA begin in mid-adult life and progress slowly over the course of many years.
OPCA is characterized by progressive degeneration of certain structures of the brain, especially the cerebellum, pons, and inferior olivae. The cerebellum is the part of the brain that plays a role in maintaining balance and posture as well as coordinating voluntary movement. The pons is part of the brainstem and contains important neuronal pathways between the cerebrum, spinal cord, and cerebellum. The pons serves as a relay point for messages between these structures. The inferior olivae are two round structures that contain nuclei that are involved with balance, coordination and motor activity.
Most types of inherited OPCA are spinocerebellar ataxias that follow autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Fickler-Winkler type OPCA and the pontocerebellar hypoplasia conditions follow autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
OPCA-X (SCA-X1) follows X-linked inheritance. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and one is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease gene he will usually develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
Males with X-linked disorders pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
The cause of sporadic OPCA is not yet defined but it is associated with abnormalities in the alpha-synuclein protein found in the deteriorating nerve cells.
OPCA is a group of rare disorders that affects males and females in equal numbers. Because of confusion regarding the naming and classification of these disorders, determining their frequency in the general population is difficult. The frequency of all forms of OPCA has been estimated to be 3-5/100,000 in the United States.
A diagnosis of OPCA is a preliminary diagnosis that is made by a thorough clinical examination and identification of characteristic symptoms. Hereditary OPCA can be diagnosed based on a family history of the same condition or by molecular genetic testing for gene mutations known to be associated with the condition. Molecular genetic testing is available for several of the SCAs. A diagnosis of sporadic OPCA is made if hereditary OPCAs and other conditions associated with symptoms of OPCA are ruled out. Testing may include blood work to rule out other conditions, MRI scans of the brain to look for degenerative changes in the brainstem, EMG testing to look at the electrical testing of muscles and nerves and sometimes examination of spinal fluid.
No specific treatment exists for individuals with OPCA. Treatment is symptomatic and supportive. Continuous medical supervision may be necessary to avoid potential complications involving the heart, lungs, spine, bone and muscle. Prevention of infection is a challenge in the care of individuals with advanced stages of OPCA.
Dopaminergic medications, which are used to treat individuals with Parkinson's disease, are sometimes used for individuals with OPCA, however often with limited benefit. The drug propranolol has been used to treat tremor associated with OPCA, also with limited benefit. Baclofen may be prescribed for spasticity.
Individuals with OCPA often receive physical, occupational and speech therapy. Devices to assist walking (e.g., canes) may be necessary in some cases.
Genetic counseling is recommended for individuals with hereditary OPCA and their family members.
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