Progressive myoclonic epilepsy
Encyclopedia
Progressive myoclonic epilepsy (PME) is a rare epilepsy
syndrome caused by a variety of genetic disorders. It consists of both myoclonic seizure
s and tonic-clonic
seizures together with progressive neurological decline.
It is also known as "progressive myoclonus epilepsy".
) and a decline in cognitive ability (dementia
).
and prevalence
of PME is unknown, but there are considerable geography and ethnic variations amongst the specific genetic disorders. One cause, Unverricht Lundborg Disease, has an incidence of at least 1:20,000 in Finland.
, such as juvenile myoclonic epilepsy
. With PME, the initial effectiveness of anticonvulsant
treatment diminishes as seizures become more frequent and neurological decline progresses. However, these can also be signs of anticonvulsant intoxication. The myoclonus in PME is usually severe and is the prominent seizure type.
; myoclonus epilepsy and ragged red fibres (MERRF syndrome)
; Lafora disease
; neuronal ceroid lipofuscinoses
; and type I sialidosis
. Less common causes include dentatorubropallidoluysian atrophy (DRPLA); the noninfantile neuronopathic form of Gaucher disease; and atypical inclusion body disease. PME has also been reported in Niemann-Pick disease type C.
, an old and commonly used anticonvulsant, is known to seriously exacerbate the condition. It has autosomal recessive inheritance, and is caused by a mutation in the cystatic B (EPM1)
gene on chromosome 21q22.3, which was discovered in 1996.
It has been described as the least severe type of PME.
and zonisamide
are first choice anticonvulsants, and the ketogenic diet
may be helpful. An autosomal-recessive genetic defect is responsible, which has been tracked down to two genes. The EPM2A gene on chromosome 6q24 was discovered in 1998 and encodes for the protein laforin
. It is responsible for 80% of cases. The EPM2B gene on chromosome 6p22.3 was discovered in 2003 and encodes for the protein malin. There may be a third gene of unknown locus.
) in the body's tissues and are inherited in an autosomal-recessive fashion. Onset and symptoms vary with the particular form, but death usually occurs within five to fifteen years.
.
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...
syndrome caused by a variety of genetic disorders. It consists of both myoclonic seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s and tonic-clonic
Tonic-clonic seizure
Tonic–clonic seizures are a type of generalized seizure that affects the entire brain...
seizures together with progressive neurological decline.
It is also known as "progressive myoclonus epilepsy".
Presentation
Myoclonic seizures involve brief involuntary muscle twitching, and may become frequent enough to be disabling. Other symptoms can include but are not limited to; uncontrollable sneezing and rapid blinking. Dwarfs are common victims of this rare but deadly disease. Tonic-clonic seizures have two phases: the tonic phase may last a few seconds and involves the muscles tensing, and may lead to the person falling down; the clonic phase involves a convulsion of rapidly alternating muscle tensing and relaxing. Neurological dysfunction includes difficulty coordinating muscle movements (ataxiaAtaxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
) and a decline in cognitive ability (dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
).
Epidemiology
PME accounts for less than 1% of epilepsy cases at specialist centres. The 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...
and prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
of PME is unknown, but there are considerable geography and ethnic variations amongst the specific genetic disorders. One cause, Unverricht Lundborg Disease, has an incidence of at least 1:20,000 in Finland.
Differential diagnosis
In the early stages, it can be difficult to distinguish progressive myoclonic epilepsy from benign idiopathic generalised epilepsiesIdiopathic generalized epilepsy
Idiopathic generalized epilepsy is a group of epileptic disorders that are believed to have a strong underlying genetic basis. Patients with an IGE subtype are typically otherwise normal and have no anatomical brain abnormalities. Patients also often have a family history of epilepsy and seem to...
, such as juvenile myoclonic epilepsy
Juvenile 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...
. With PME, the initial effectiveness of anticonvulsant
Anticonvulsant
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...
treatment diminishes as seizures become more frequent and neurological decline progresses. However, these can also be signs of anticonvulsant intoxication. The myoclonus in PME is usually severe and is the prominent seizure type.
Specific disorders
Six specific disorders comprise the most common causes of progressive myoclonic epilepsy: Unverricht-Lundborg disease (Baltic myclonus)Unverricht-Lundborg disease
Unverricht-Lundborg disease 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...
; myoclonus epilepsy and ragged red fibres (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
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 lipofuscinoses
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...
; and type I 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...
. Less common causes include dentatorubropallidoluysian atrophy (DRPLA); the noninfantile neuronopathic form of Gaucher disease; and atypical inclusion body disease. PME has also been reported in Niemann-Pick disease type C.
Unverricht-Lundborg disease
This disease manifests between six and sixteen years and is most prevalent in Scandinavia and the Baltic countries. Myoclonus gradually becomes worse and less susceptible to medication. Cognitive decline is slow and sometimes mild. Patients typically do not live beyond middle-age, but there are exceptions. 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...
, an old and commonly used anticonvulsant, is known to seriously exacerbate the condition. It has autosomal recessive inheritance, and is caused by a mutation in the cystatic B (EPM1)
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 on chromosome 21q22.3, which was discovered in 1996.
It has been described as the least severe type of PME.
Myoclonus epilepsy and ragged red fibres (MERRF syndrome)
Onset of this disease may be at any time and the severity and progression are varied. Tonic-clonic seizures and dementia are less apparent than with other forms of PME. The cause is a mitochondrial DNA mutation, so most familial cases are transmitted from the mother. A skeletal muscle biopsy will show ragged red fibres, hence the name.Lafora body disease
This disease typically begins between six and nineteen years after apparently normal development and generally results in death within ten years. It is characterised by the presence of Lafora bodies (polyglucosan inclusions) in neurones and other body tissue. The generalised seizures are usually well controlled by anticonvulsants, but the myoclonus soon proves refractory to treatment. Within a couple of years, a wheelchair is required for locomotion and within five to ten years, the person is confined to bed and is often tube fed. 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...
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:...
are first choice anticonvulsants, and the ketogenic diet
Ketogenic diet
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control epilepsy in children. The diet mimics aspects of starvation by forcing the body to burn fats rather than carbohydrates...
may be helpful. An autosomal-recessive genetic defect is responsible, which has been tracked down to two genes. The EPM2A gene on chromosome 6q24 was discovered in 1998 and encodes for the protein laforin
Laforin
Laforin, encoded by the EPM2A gene, is a protein mutated in patients with Lafora disease. It contains a dual specificity phosphatase domain and a carbohydrate binding module subtype 20 . Its physiological substrate has yet to be identified and the molecular mechanisms in which mutated laforin...
. It is responsible for 80% of cases. The EPM2B gene on chromosome 6p22.3 was discovered in 2003 and encodes for the protein malin. There may be a third gene of unknown locus.
Neuronal ceroid lipofuscinoses
There are various forms of these disorders, each with their own genetic cause and geographical variation, which lead to accumulation of lipopigments (lipofuscinLipofuscin
Lipofuscin is the name given to finely granular yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion. It is considered one of the aging or "wear-and-tear" pigments, found in the liver, kidney, heart muscle, adrenals, nerve cells, and ganglion cells...
) in the body's tissues and are inherited in an autosomal-recessive fashion. Onset and symptoms vary with the particular form, but death usually occurs within five to fifteen years.
Type I sialidosis
This is an autosomal recessive disorder in which the body is deficient in α-neuraminidaseNeuraminidase
Neuraminidase enzymes are glycoside hydrolase enzymes that cleave the glycosidic linkages of neuraminic acids. Neuraminidase enzymes are a large family, found in a range of organisms. The most commonly known neuraminidase is the viral neuraminidase, a drug target for the prevention of the spread...
.