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Progressive myoclonus epilepsy (PME) is a group of conditions involving the central nervous system and representing more than a dozen different diseases. These diseases share certain features, including a worsening of symptoms over time and the presence of both muscle contractions (myoclonus) and seizures (epilepsy). Patients may have more than one type of seizure, such as petit mal or grand mal. PME is progressive, but the rate of progression may be quick or slow, depending on the underlying disease.
Progressive myoclonus epilepsy (PME) is different from myoclonic epilepsy. In myoclonic epilepsy, the myoclonic jerking motions occur as part of the seizure. In PME, myoclonus occurs separately from seizures, the two respond differently to the same drugs, they evolve differently during the natural history of the disease, and they cause different problems for the patient. Some drugs that are good for seizures, e.g. phenytoin and carbamazepine, may tend to make the myoclonus worse.
Myoclonus is usually a greater problem than seizures for patients with PME because it is not helped much by the anticonvulsants that do help to control the seizures. The twitching occurs more frequently in the early part of the day or when the patient is under stress of various sorts. Positive myoclonus alludes to jerking of the hands and arms. Negative myoclonus refers to the sudden onset of loss of control of the muscles of the legs that leads to falls and injuries. As the frequency of myoclonic jerks increases, it may build to a "crescendo myoclonus" or a convulsion, after which the condition improves for a few days.
Lack of motor coordination may occur along with myoclonus, even in the absence of seizures. Mental function may be impaired, leading especially to problems with memory. Depression is not uncommon. It can become severe and should not be left untreated.
Other problems may include a bladder abnormality that may be associated with urinary tract infection. Depending on the type of PME, patients may also experience gastrointestinal and thyroid problems, as well as vision or hearing impairment. Weight control may be a problem for inactive patients.
There are many different types of PME, each with a different underlying cause. The types of PME include the following:
EPM1 (epilepsy, progressive myoclonus 1) or myoclonic epilepsy of Unverricht and Lundborg
EPM2A (epilepsy, progressive myoclonus 2) or myoclonic epilepsy of Lafora
Batten disease (neuronal ceroid lipofuscinosis)
Cerebral storage and degenerative disorders
(For more information on these disorders, choose the disorder name as your search term in the Rare Disease Database.)
EPM1 (Unverricht-Lundborg disease) usually presents between the ages of six and thirteen with the advent of convulsions. Myoclonus begins one to five years later when muscle spasms of the limbs and minor twitching motions become obvious. Later, these spasms may become so violent that the patient falls. Mental deterioration accompanies the disease progression. However, the progression of the disease in EPM1 is slower than in most other forms of the syndrome.
The duration and seriousness of EPM1 are variable. In advanced cases, inability to coordinate voluntary muscle movements (cerebellar ataxia) occurs. Very rarely, deafness may occur, especially when cerebellar ataxia is present. Emotional instability is common. In EPM1, there are no particles in brain or other tissue cells as in Lafora's disease. However the area of the brain concerned with muscle coordination and balance shows a loss of nerve cells. Changes in the environment like flashing lights or the flickering of sunlight may cause the worst symptoms (stimulus-sensitive myoclonus). Other features are generalized tonic-clonic seizures that are sometimes combined with absence attacks (petit mal). These types of seizures may be documented by EEG readings. EPM1 is an autosomal recessive genetic disease caused by mutations in the CSTB gene.
EPM2A (Lafora disease) presents in the form of grand mal seizures and/or myoclonus, usually during the teen years. It is characterized by the presence of carbohydrate particles (Lafora bodies) in cells of the nervous system (brain, spinal cord, or nerves), muscle (or muscle fibers), and/or skin. The presence of Lafora bodies in biopsied tissue is diagnostic. Over time, mental deterioration may occur and grand mal seizures become more frequent. EPM2A is one of the more severe forms of PME. EPM2A is an autosomal recessive genetic disorder caused by mutations in the EPM2A gene or NHLRC1 gene.
Mitochondrial myopathies are a group of neurological and neuromuscular disorders that arise from genetic mutations affecting the function of intracellular (within the cell capsule) energy-producing particles (mitochondria). Since mitochondria are found in the cells of most tissues, diagnosis of these disorders is made though the use of blood chemistry tests or through muscle biopsies.
Batten Disease refers to a family of about seven disorders called the neuronal ceroid lipofuscinoses.
Cerebral storage and degenerative disorders often are accompanied by PME. Among these are several disorders that result from the storage of inappropriate intermediate metabolites in the lysosomes of cells. The accumulation (storage) of these metabolites occurs because an essential enzyme, needed to further metabolize the accumulated chemicals, is not present or is present in insufficient concentration. Gene mutations are the cause of these metabolic disorders. Tay-Sachs disease and Gaucher’s disease are examples of this group of conditions.
Biotin-responsive disorders often present with PME that, in these cases, is frequently reversible. Biotin is essential for several enzymes to keep brain metabolism proceeding smoothly. Normally, biotin is recycled and levels are sustained. If the enzymes required for recycling the biotin are not available, then the condition is called biotinidase deficiency. The condition can be diagnosed through blood chemistry to measure the levels of biotin, biotinidase and biotin-dependent enzymes.
There are many different types of PME, each with a different underlying cause.
EPM1 is an autosomal recessive genetic disease caused by mutations in the CSTB gene.
EPM2A is an autosomal recessive genetic disorder caused by mutations in the EPM2A gene or NHLRC1 gene.
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.
Mitochondrial disorders may be caused by defects of nuclear DNA or mitochondrial DNA. Nuclear gene defects may be inherited in an autosomal recessive manner or an autosomal dominant manner. Mitochondrial DNA defects are transmitted by maternal inheritance. Genes have ben identified that are associated with some mitochondrial myopathies.
Gene mutations have been discovered for some of the forms of Batten disease.
EPM1 occurs throughout the world but the prevalence is highest in the North African countries of Tunisia, Algeria and Morocco and also in Finland. The prevalence in Finland is approximately 1/20,000 births.
EPM2A occurs worldwide but estimates of prevalence are not available. This condition is known to occur more often in the Mediterranean basin of Spain, France and Italy and in some areas of central Asia, India, Pakistan, northern Africa and the Middle East where marriage within families is common.
Symptoms of the following disorders can be similar to those of Progressive Myoclonus Epilepsy. Comparisons may be useful for a differential diagnosis:
In general, myoclonus is a group of movement disorders characterized by sudden, involuntary contractions of a skeletal muscle or group of muscles. It may be divided into two groups, rhythmical and arrhythmic myoclonus. Myoclonus may accompany a number of neurological diseases including seizure disorders, brain injuries, hereditary brain disorders, viral infections, and brain tumors. Hereditary, and idiopathic forms also exist. In Postanoxic Myoclonus the disorder begins after the brain is deprived of oxygen. (For more information about other types of myoclonus, choose "myoclonus" as your search term in the Rare Disease Database.)
In Juvenile Myoclonic Epilepsy, the age of onset is early. It is characterized by the presence of isolated myoclonic jerks that do not necessarily lead to major seizures. These symptoms usually occur in the morning. There may be a record of epilepsy in the family history. In some cases there is evidence that this form of epilepsy is inherited through autosomal recessive genes. Juvenile Myoclonic Epilepsy is often diagnosed through use of electroencephalography (EEG) which demonstrates evidence of the illness even when no seizures are present. Occasionally, some family members who show no outward symptoms of the disorder will show the same EEG characteristics. This disorder is chronic but not progressive.
Huntington's Disease (also known as Huntington's Chorea) is an inherited, progressively degenerative neurological illness. Those affected experience abnormal involuntary movements (chorea), loss of motor control, changes in gait, loss of memory, and eventual loss of both mental capacity and physical control. In general, onset of HD occurs in adults between thirty and fifty years of age and runs a progressive course, severely weakening patients usually over a ten to twenty year period. (For more information on this disorder, choose "Huntington's Disease" as your search term in the Rare Disease Database.)
Tourette Syndrome is a neurological movement disorder that begins in childhood between the ages of 2 and 16. The disease is characterized by involuntary, abrupt, muscular movements called " tics", and uncontrollable vocal sounds. Sometimes inappropriate words may occur. Tourette Syndrome is not a degenerative disorder and those affected can expect to live a normal life span. (For more information on this disorder, choose "Tourette Syndrome" as your search term in the Rare Disease Database.)
Wilson's Disease is a rare genetic disorder characterized by excess storage of copper in the body tissues, particularly in the liver, brain, and corneas of the eyes. It eventually leads to liver disease, neurological abnormalities such as seizures, and a characteristic rusty-brown colored ring in the cornea of the eyes known as Kayser-Fleischer rings. Involuntary abnormal movements, particularly tremor and chorea, and behavioral changes are early symptoms of this disorder. (For more information on this disorder, choose "Wilson" as your search term in the Rare Disease Database.)
The following disorders may be associated with Progressive Myoclonus Epilepsy. They are not necessary for a differential diagnosis:
Kufs Disease is a very rare disorder of the central nervous system marked initially by progressive weakness with diminished muscle coordination, seizures, rapid involuntary jerky movements and rarely blindness. This disorder can be inherited as either a dominant or recessive trait and is usually slowly progressive. (For more information on this disorder, choose "Kufs Disease" as your search term in the Rare Disease Database.)
Ramsay-Hunt Syndrome is an autosomal dominant disorder in which epilepsy and myoclonus accompany significant spinocerebellar degeneration and other progressive neurological abnormalities. (For more information on this disorder, choose "Ramsay" as your search term in the Rare Disease Database.)
Progressive myoclonus epilepsy is diagnosed by clinical findings and Electroencephalogram (EEG) results. Molecular genetic testing is available for genes associated with EPM1, EPM2A, and for some of the genes associated with other types of PME.
Treatment of progressive myoclonus epilepsy includes the anticonvulsant drugs clonazepam, divalproex, and primidone in much the same dosages used to treat epilepsy. In all cases, the better advice is to start with low doses and work upwards. The diets of patients taking divalproex chronically should be supplemented with carnitine.
Low dose oral contraceptives may be of help to women who experience heightened myoclonus or seizures during menstruation.
Phenytoin, carbamazepine, and lamotrigine are drugs to be avoided since they may make the myoclonus worse and/or damage parts of the cerebellum even further.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
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FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM), Johns Hopkins University.
Myoclonic Epilepsy of Unverricht and Lundborg. OMIM No: 254800; Last Update: 2/21/02
Epilepsy, Progressive Myoclonic 2; EPM2A. OMIM No: 254780; Last Update: 5/9/01
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Report last updated: 2008/01/29 00:00:00 GMT+0