Unverricht-Lundborg disease
Encyclopedia
Unverricht-Lundborg disease (abbreviated ULD or EPM1) is the most common form of an uncommon group of genetic
epilepsy
disorders called progressive myoclonic epilepsy
. It is caused due to a mutation in the cystatin B
gene (CSTB). The disease is named after Heinrich Unverricht
, who first described it in 1891, and Herman Bernhard Lundborg
, who researched it in greater detail in 1903. ULD onsets in children between the ages of 6 and 16; there are no known cases in which the person was older than 18. Most cases originate from the Baltic region of Europe, though many have been reported from countries in the Mediterranean.
Onset of the disease is characterized by myoclonic jerks
and tonic-clonic seizure
s. Early cases often resulted in the need of a wheelchair and death before the age of 24, but new treatments and medications have increased the life expectancy of individuals with ULD, in some cases even to near that of an unaffected individual.
, Lafora disease (EPM2a or EMP2b)
, Neuronal ceroid lipofuscinosis
(NCL) and sialidosis
. Progressive myoclonic epilepsies generally constitute only a small percentage of epilepsy cases seen, and ULD is the most common form. While ULD can lead to an early death, it is considered to be the least severe form of progressive myoclonic epilepsy.
(JME).
.
neurons. It has shown that a lack of cystatin B due to a mutation of the CSTB gene leads to a decrease in the number of inhibitory neurons, and this lack of inhibition makes the cells in the brain, particularly the hippocampus
, more excitable. It is hypothesized that this increase in excitability is what causes the myoclonic jerks and tonic-clonic seizures in patients with ULD.
, fosphenytoin
, sodium channel blockers, GABAergic drugs
, gabapentin
and pregabalin
.
Other methods to diagnose Unverricht-Lundborg disease are currently being explored. While electroencephalogram (EEG) is useful in identifying or diagnosing other forms of epilepsy, the location of seizures in ULD is currently known to be generalized across the entire brain. Without a specific region to pinpoint, it is difficult to accurately distinguish an EEG reading from an individual with ULD from an individual with another type of epilepsy characterized by generalized brain seizures. However, with recent research linking ULD brain damage to the hippocampus, the usefulness of EEG as a diagnostic tool may increase.
Magnetic Resonance Imaging (MRI) is also often used during diagnosis of patients with epilepsy. While MRIs taken during the onset of the disease are generally similar to those of individuals without ULD, MRIs taken once the disease has progressed show characteristic damage, which may help to correct a misdiagnosis.
While ULD is a rare disease, the lack of well defined cases to study and the difficulty in confirming diagnosis provide strong evidence that this disease is likely under diagnosed.
are effective in reducing seizures and helping patients with ULD to manage the symptoms. In addition, new research is being performed to examine the effectiveness of other types of treatments.
is the first line drug choice for reducing generalised seizures and myoclonus
. Levetiracetam is also effective for both generalised seizures and myoclonus. Clonazepam
and high-dose piracetam
can alleviate myoclonus. Phenytoin
can worsen seizures and may speed up neurodegeneration
; carbamazepine
, oxcarbazepine
, tiagabine
, vigabatrin
, gabapentin
and pregabalin
may worsen myoclonus and myoclonic seizures. Other common medications to treat ULD include topiramate
and zonisamide
. If an individual with Unverricht-Lundborg disease is particularly sensitive to a certain type of stimulus, it is also beneficial to reduce the patient's exposure to that stimulus in order to reduce the likelihood of seizures. Since ULD is progressive and may not get better over time, depression has been documented in many cases, so providing a strong support group of friends, family, and even other individuals with ULD is very beneficial.
, so it is necessary to attach it to another molecule. While the study was not able to get cystatin B past the blood-brain barrier, this method still exists as a viable option to treat ULD if the correct binding molecule is found.
However, increased knowledge about the disease and improved treatment and medication has led to a drastic improvement in prognosis for individuals with ULD. Antiepileptic drugs reduce the occurrence of seizures and myoclonus, which leads to a decrease in the damage caused in the brain due to seizures and the body due to falls resulting from the seizures. As a result, individuals with Unverricht-Lundborg disease are now much less likely to end up in a wheelchair, which eliminates the chance of complications involved with being a wheelchair user. All these factors have increased the outlook for patients. Due to the progressive nature of the disease, depression is prevalent, but support of family and friends as well as proper treatment can help. While early patients with ULD had a life expectancy of around 24 years, there have recently been reported cases of individuals living to near-normal ages.
is in Finland, where it is reported to occur in 4 in 100,000 individuals. However, ULD has only become well defined recently, and it is likely still under diagnosed, so the actual incidence may be different that what is currently known. Other countries with known cases include countries in the Mediterranean region including Italy, France, Tunisia, Algeria, and Morocco, as well as the United States.
(EEG) is not very effective as a diagnostic tool for Unverricht-Lundborg disease. This study instead looks to characterize the change in EEG of ULD patients as the disease progresses. The researchers studied twenty-five patients with ULD and monitored their EEG over time. The results show that certain brain waves that are present at the beginning of ULD progression and are also present in unaffected individuals, including spontaneous generalized spike or polyspike wave discharges and photoparoxysmal response, tend to decrease after 10 to 15 years.
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
disorders called progressive myoclonic epilepsy
Progressive myoclonic epilepsy
Progressive myoclonic epilepsy is a rare epilepsy syndrome caused by a variety of genetic disorders. It consists of both myoclonic seizures and tonic-clonic seizures together with progressive neurological decline....
. It is caused due to a mutation in the cystatin B
Cystatin B
Cystatin-B is a protein that in humans is encoded by the CSTB gene.-Interactions:Cystatin B has been shown to interact with Cathepsin B.-External Links:* * The MEROPS online database for peptidases and their inhibitors:...
gene (CSTB). The disease is named after Heinrich Unverricht
Heinrich Unverricht
Heinrich Unverricht was a German internist who was a native of Breslau. In 1877 he obtained his doctorate from the University of Breslau, where he was a student of Michael Anton Biermer...
, who first described it in 1891, and Herman Bernhard Lundborg
Herman Bernhard Lundborg
Herman Bernhard Lundborg was a Swedish physician. He graduated in medicine at the Karolinska Institutet in 1895, and received his doctorate at the Uppsala University in 1903...
, who researched it in greater detail in 1903. ULD onsets in children between the ages of 6 and 16; there are no known cases in which the person was older than 18. Most cases originate from the Baltic region of Europe, though many have been reported from countries in the Mediterranean.
Onset of the disease is characterized by myoclonic jerks
Myoclonus
Myoclonus is brief, involuntary twitching of a muscle or a group of muscles. It describes a medical sign and, generally, is not a diagnosis of a disease. Brief twitches are perfectly normal. The myoclonic twitches are usually caused by sudden muscle contractions; they also can result from brief...
and tonic-clonic seizure
Tonic-clonic seizure
Tonic–clonic seizures are a type of generalized seizure that affects the entire brain...
s. Early cases often resulted in the need of a wheelchair and death before the age of 24, but new treatments and medications have increased the life expectancy of individuals with ULD, in some cases even to near that of an unaffected individual.
Classification
Unverricht-Lundborg disease is also known as EPM1, as it is a form of progressive myoclonic epilepsy (PME). Other progressive myoclonic epilepsies include myoclonus epilepsy and ragged red fibers (MERRF syndrome)MERRF syndrome
MERRF syndrome is a mitochondrial disease. It is extremely rare, with an estimated prevalence of 1/400,000 in Europe, and has varying degrees of expressivity owing to heteroplasmy-Presentation:...
, Lafora disease (EPM2a or EMP2b)
Lafora disease
Lafora disease, also called Lafora progressive myoclonic epilepsy or MELF , is a fatal autosomal recessive genetic disorder characterized by the presence of inclusion bodies, known as Lafora bodies, within neurons and the cells of the heart, liver, muscle, and skin.Most patients with this disease...
, Neuronal ceroid lipofuscinosis
Neuronal Ceroid Lipofuscinosis
Neuronal Ceroid Lipofuscinoses is the general name for a family of at least eight genetically separate neurodegenerative disorders that result from excessive accumulation of lipopigments in the body's tissues. These lipopigments are made up of fats and proteins...
(NCL) and sialidosis
Sialidosis
Mucolipidosis type I or sialidosis is an inherited lysosomal storage disease that results from a deficiency of the enzyme sialidase. The lack of this enzyme results in an abnormal accumulation of complex carbohydrates known as mucopolysaccharides, and of fatty substances known as mucolipids...
. Progressive myoclonic epilepsies generally constitute only a small percentage of epilepsy cases seen, and ULD is the most common form. While ULD can lead to an early death, it is considered to be the least severe form of progressive myoclonic epilepsy.
Signs and symptoms
Patients with Unverricht-Lundborg disease exhibit myoclonic jerks and tonic-clonic seizures at a young age, between ages 6-16. The myoclonic jerks occur in the muscles of the arms and legs closest to the torso, and are triggered due to a variety of common external stimuli. Seizures begin at an average age of 10.8 years, with myoclonus beginning around 12.1 years. It is not currently possible to diagnose without a genetic test, and since early symptoms are general, it is often mistaken for another more common epilepsy, in many cases juvenile myoclonic epilepsyJuvenile myoclonic epilepsy
Juvenile myoclonic epilepsy , also known as Janz syndrome, is a fairly common form of idiopathic generalized epilepsy, representing 5-10% of all epilepsies. This disorder typically first manifests itself between the ages of 12 and 18 with myoclonus occurring early in the morning. Most patients also...
(JME).
Causes
The genetic cause of ULD is known, but research has led to new areas of study that may lead to an increase in knowledge of what causes ULD.Genetic Factors
The cause of ULD is known to be a mutation of the gene that produces cystatin B. The disease is autosomal recessive, so both parents of an individual must be carriers of the recessive CSTB gene for the individual to inherit it, and for an individual to show symptoms of ULD, they must have both recessive CSTB genes. Siblings of affected individuals who only have one recessive gene have been monitored and generally do not show the signs of ULD, though in some cases mild symptoms may be present.New Developments
New research shows that cystatin B may not be the only factor involved in Unverricht-Lundborg disease. In a study, it was determined that patients with ULD had more dopamine receptors in certain areas of their brain than unaffected individuals. The researchers chose to investigate dopamine receptors because they are known to be a factor in myoclonus, which are a significant part of the symptoms of ULD. The results of this study indicate that the cause of ULD may be more complex that currently thought.Mechanism
While the genetic cause of Unverricht-Lundborg disease is known, the mechanism by which it works is not fully known. Current research has provided promising results that may lead to a confirmation of the mechanism. This research has been performed on mice with the gene for producing cystatin B removed, to provide a similar set of symptoms to individuals with ULD. The mechanism currently supported by research is very similar to another theory of epilepsy progression known as kindlingKindling model
Kindling is a commonly used model for the development of seizures and epilepsy in which the duration and behavioral involvement of induced seizures increases after seizures are induced repeatedly. The kindling model was first proposed in the late 1960s by Goddard and colleagues...
.
Onset
Current research links cystatin B to production of inhibitory neurons known as GABAergicGamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
neurons. It has shown that a lack of cystatin B due to a mutation of the CSTB gene leads to a decrease in the number of inhibitory neurons, and this lack of inhibition makes the cells in the brain, particularly the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, more excitable. It is hypothesized that this increase in excitability is what causes the myoclonic jerks and tonic-clonic seizures in patients with ULD.
Progression
Research also gives evidence to support the idea that cystatin B may be a type of "protecting" molecule in the brain. Normally, after a seizure, the presence of cystatin B prevents the neurons from dying due to toxic levels of neurotransmitters. Studies suggest that the absence of cystatin B leads to the death of affected neurons, leading to a damaged portion of the brain. This damage coupled with the increased excitability of the cells then leads to more damage, which is what makes Unverricht-Lundborg disease progressive.Diagnosis
The only currently available method to diagnose Unverricht-Lundborg disease is a genetic test to check for the presence of the mutated cystatin B gene. If this gene is present in an individual suspected of having the disease, it can be confirmed. However, genetic tests of this type are prohibitively expensive to perform, especially due to the rarity of ULD. The early symptoms of ULD are general and in many cases similar to other more common epilepsies, such as juvenile myoclonic epilepsy. For these reasons, ULD is generally one of the last options doctors explore when looking to diagnose patients exhibiting its symptoms. In most cases, a misdiagnosis is not detrimental to the patient, because many of the same medications are used to treat both ULD and whatever type of epilepsy the patient has been misdiagnosed with. However, there are a few epilepsy medications that increase the incidence of seizures and myoclonic jerks in patients with ULD, which can lead to an increase in the speed of progression, including phenytoinPhenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
, fosphenytoin
Fosphenytoin
Fosphenytoin is a water-soluble phenytoin prodrug used only in hospitals for the treatment of epileptic seizures....
, sodium channel blockers, GABAergic drugs
GABA agonist
A GABA agonist is a drug which acts to stimulate or increase the action at the GABA receptor, producing typically sedative effects, and may also cause other effects such as anxiolytic and muscle relaxant effects.Examples include:* Acamprosate* Picamilon...
, gabapentin
Gabapentin
Gabapentin is a pharmaceutical drug, specifically a GABA analogue. It was originally developed for the treatment of epilepsy, and currently is also used to relieve neuropathic pain...
and pregabalin
Pregabalin
Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for generalized anxiety disorder and is approved for this use in the European Union. It was designed...
.
Other methods to diagnose Unverricht-Lundborg disease are currently being explored. While electroencephalogram (EEG) is useful in identifying or diagnosing other forms of epilepsy, the location of seizures in ULD is currently known to be generalized across the entire brain. Without a specific region to pinpoint, it is difficult to accurately distinguish an EEG reading from an individual with ULD from an individual with another type of epilepsy characterized by generalized brain seizures. However, with recent research linking ULD brain damage to the hippocampus, the usefulness of EEG as a diagnostic tool may increase.
Magnetic Resonance Imaging (MRI) is also often used during diagnosis of patients with epilepsy. While MRIs taken during the onset of the disease are generally similar to those of individuals without ULD, MRIs taken once the disease has progressed show characteristic damage, which may help to correct a misdiagnosis.
While ULD is a rare disease, the lack of well defined cases to study and the difficulty in confirming diagnosis provide strong evidence that this disease is likely under diagnosed.
Treatment
While there is no current cure to repair the mutated CSTB gene, several antiepileptic drugsAnticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
are effective in reducing seizures and helping patients with ULD to manage the symptoms. In addition, new research is being performed to examine the effectiveness of other types of treatments.
Current methods
Valproic acidValproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
is the first line drug choice for reducing generalised seizures and myoclonus
Myoclonus
Myoclonus is brief, involuntary twitching of a muscle or a group of muscles. It describes a medical sign and, generally, is not a diagnosis of a disease. Brief twitches are perfectly normal. The myoclonic twitches are usually caused by sudden muscle contractions; they also can result from brief...
. Levetiracetam is also effective for both generalised seizures and myoclonus. Clonazepam
Clonazepam
Clonazepamis a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties. It is marketed by Roche under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe...
and high-dose piracetam
Piracetam
Piracetam is a nootropic drug. Piracetam's chemical name is 2-oxo-1-pyrrolidine acetamide; it shares the same 2-oxo-pyrrolidone base structure with 2-oxo-pyrrolidine carboxylic acid . Piracetam is a cyclic derivative of GABA. It is one of the group of racetams...
can alleviate myoclonus. Phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
can worsen seizures and may speed up neurodegeneration
Neurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
; carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
, oxcarbazepine
Oxcarbazepine
Oxcarbazepine is a anticholinergic anticonvulsant and mood stabilizing drug, used primarily in the treatment of epilepsy. It is also used to treat anxiety and mood disorders, and benign motor tics...
, tiagabine
Tiagabine
Tiagabine -Indications:Tiagabine is approved by U.S. Food and Drug Administration as an adjunctive treatment for partial seizures in ages 12 and up. It may also be prescribed to treat anxiety disorders and neuropathic pain . For anxiety and neuropathic pain, tiagabine is used primarily to augment...
, vigabatrin
Vigabatrin
Vigabatrin is an antiepileptic drug that inhibits the catabolism of gamma-aminobutyric acid by irreversibly inhibiting GABA transaminase. It is an analog of GABA, but it is not a receptor agonist...
, gabapentin
Gabapentin
Gabapentin is a pharmaceutical drug, specifically a GABA analogue. It was originally developed for the treatment of epilepsy, and currently is also used to relieve neuropathic pain...
and pregabalin
Pregabalin
Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for generalized anxiety disorder and is approved for this use in the European Union. It was designed...
may worsen myoclonus and myoclonic seizures. Other common medications to treat ULD include topiramate
Topiramate
Topiramate is an anticonvulsant drug. It was originally produced by Ortho-McNeil Neurologics and Noramco, Inc., both divisions of the Johnson & Johnson Corporation. This medication was discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil...
and zonisamide
Zonisamide
Zonisamide is a sulfonamide anticonvulsant approved for use as an adjunctive therapy in adults with partial-onset seizures for adults; infantile spasm, mixed seizure types of Lennox-Gastaut syndrome, myoclonic, and generalized tonic clonic seizure.-History:...
. If an individual with Unverricht-Lundborg disease is particularly sensitive to a certain type of stimulus, it is also beneficial to reduce the patient's exposure to that stimulus in order to reduce the likelihood of seizures. Since ULD is progressive and may not get better over time, depression has been documented in many cases, so providing a strong support group of friends, family, and even other individuals with ULD is very beneficial.
New treatment opportunities
Instead of addressing the symptoms, another direction of Unverricht-Lundborg disease treatment involves correcting the deficiency in cystatin B by delivering it to the brain from an outside source. One recent study has attempted this, by attaching cystatin B to another molecule that the brain usually allows to pass. Cystatin B alone is not able to pass through the blood-brain barrierBlood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
, so it is necessary to attach it to another molecule. While the study was not able to get cystatin B past the blood-brain barrier, this method still exists as a viable option to treat ULD if the correct binding molecule is found.
Prognosis
For early Unverricht-Lundborg disease patients, the disease would begin to progress early and lack of effective treatment meant a quick progression. In many cases the patient would require a wheelchair for mobility, and would die at a young age.However, increased knowledge about the disease and improved treatment and medication has led to a drastic improvement in prognosis for individuals with ULD. Antiepileptic drugs reduce the occurrence of seizures and myoclonus, which leads to a decrease in the damage caused in the brain due to seizures and the body due to falls resulting from the seizures. As a result, individuals with Unverricht-Lundborg disease are now much less likely to end up in a wheelchair, which eliminates the chance of complications involved with being a wheelchair user. All these factors have increased the outlook for patients. Due to the progressive nature of the disease, depression is prevalent, but support of family and friends as well as proper treatment can help. While early patients with ULD had a life expectancy of around 24 years, there have recently been reported cases of individuals living to near-normal ages.
Epidemiology
The only country that Unverricht-Lundborg disease has a reported incidenceIncidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
is in Finland, where it is reported to occur in 4 in 100,000 individuals. However, ULD has only become well defined recently, and it is likely still under diagnosed, so the actual incidence may be different that what is currently known. Other countries with known cases include countries in the Mediterranean region including Italy, France, Tunisia, Algeria, and Morocco, as well as the United States.
History
Unverricht-Lundborg disease was first known as one of two different diseases, depending on the location of the individual who had it: Baltic myoclonus or Mediterranean myoclonus. The reason for the different names was partly regional but also because the prognosis of the disease was different for individuals with each due to the way that it was treated in that region. Eventually, both were realized to be the same disease, ULD.Research directions
Many studies have been performed recently to investigate the cause, mechanism, and chemical basis of Unverricht-Lundborg disease.Cystatin B Characteristics
A recent study has attempted to describe the behavior of normal and mutated cystatin B as it is expressed in the body. The results show that cystatin B has a polymeric structure, and that the mutated form of cystatin B, which is present in patients with Unverricht-Lundborg disease, is likely to attract other molecules of cystatin B and form clumps of the molecule. The researchers suggest that this clotting action of the cystatin B molecules may be one of the factors that cause progression of ULD.Study of Heterozygous Mice
In humans it is generally known that unless a patient has both recessive CSTB genes (are homozygous recessive), they will not express ULD symptoms. A recent study has attempted to characterize the effects, if any, seen in mice that carry only one recessive CSTB gene (are heterozygous). The researchers analyzed normal and heterozygous mice by having them perform various tasks. The study found that heterozygous mice performed similar to normal mice when the task was started, but as the task continued or became more complex they were more likely to fail. While the results for the heterozygous mice were not remarkably different from the normal mice, they do indicate that carrying just one recessive CSTB gene may have adverse effects, at least in mice.Analysis of EEG as ULD Progresses
Currently, electroencephalographyElectroencephalography
Electroencephalography is the recording of electrical activity along the scalp. EEG measures voltage fluctuations resulting from ionic current flows within the neurons of the brain...
(EEG) is not very effective as a diagnostic tool for Unverricht-Lundborg disease. This study instead looks to characterize the change in EEG of ULD patients as the disease progresses. The researchers studied twenty-five patients with ULD and monitored their EEG over time. The results show that certain brain waves that are present at the beginning of ULD progression and are also present in unaffected individuals, including spontaneous generalized spike or polyspike wave discharges and photoparoxysmal response, tend to decrease after 10 to 15 years.