Progressive Myoclonic Epilepsies (PME) are a rare group of inherited neurodegenerative diseases characterized by

myoclonus Myoclonus is a brief, involuntary, irregular (lacking rhythm) twitching of a muscle, a joint, or a group of muscles, different from clonus, which is rhythmic or regular. Myoclonus ( myo- "muscle", clonus "spasm") describes a medical sign and, ...

, resistance to treatment, and neurological deterioration. The cause of PME depends largely on the type of PME. Most PMEs are caused by

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

or recessive and mitochondrial mutations. The location of the mutation also affects the inheritance and treatment of PME. Diagnosing PME is difficult due to their

genetic heterogeneity Genetic heterogeneity refers to different genetic causes for the same disease and can be classified into three types: allelic heterogeneity, locus heterogeneity, and phenotypic heterogeneity. Allelic heterogeneity occurs when different mutations wi ...

and the lack of a genetic mutation identified in some patients. The prognosis depends largely on the worsening symptoms and failure to respond to treatment. There is no current cure for PME and treatment focuses on managing myoclonus and

seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

s through antiepileptic medication (AED). The age of onset depends on the specific PME but PME can affect people of all ages. In Unverricht-Lundborg disease (ULD) the age of onset is between 6–15 years, while in Adult Neuronal ceroid lipofuscinoses (Adult NCL) the age of onset can be as late as 30. Symptoms often include action or stimuli induced

neuropathy Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...

, cognitive decline, and spike and wave or no cerebral discharges. The prognosis of those diagnosed with PME is poor. The person often becomes reliant on a wheelchair, enters a vegetative state due to myoclonus, and has a shortened life expectancy.

Signs and symptoms

The most common symptom of PME is myoclonus. The myoclonus can be fragmented or multifocal and can be triggered by posture, actions, and external stimuli such as light, sound, and touch. The type of myoclonus differs between the types of PME. Other symptoms of PME include generalized, tonic clonic, tonic, and atypical absence seizures. In Lafora's disease the seizures are

occipital The occipital bone () is a cranial dermal bone and the main bone of the occiput (back and lower part of the skull). It is trapezoidal in shape and curved on itself like a shallow dish. The occipital bone lies over the occipital lobes of the cere ...

and the person experiences transient blindness as well as visual

hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...

s. The person may also have atypical absences and atonic and complex partial seizures. In Myoclonus epilepsy with ragged-red fibers ( MERRF) the person experiences generalized epilepsy along with myoclonus, weakness, and

dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...

. As PME progresses neurological ability decreases and can lead to

myopathy In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meaning implies that the primary defec ...

, cognitive decline,

cerebellar ataxia Cerebellar ataxia is a form of ataxia originating in the cerebellum. Non-progressive congenital ataxia (NPCA) is a classical presentation of cerebral ataxias. Cerebellar ataxia can occur as a result of many diseases and may present with symptoms ...

, and

. The different symptoms in each of the PME and between individuals makes diagnosis difficult. Therefore, diagnosis of PME is dependent on failure to respond to

antiepileptic drugs Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatment ...

and therapy but diagnosis of specific PME depends on

genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

EEG Electroencephalography (EEG) is a method to record an electrogram of the spontaneous electrical activity of the brain. The bio signals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in the neoc ...

(electroencephalography),

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

measurements and more.

Diagnosis

Diagnosis of PME is based on the individual's signs and symptoms as well as failure to respond to antiepileptic drugs and therapy. Further diagnosis support includes EEG results, genetic testing, enzyme testing, and skin and muscle biopsies. Gaucher's disease can be diagnosed through enzyme testing as it is a metabolic disease. Lafora's disease can be diagnosed using skin biopsies. While Action myoclonus renal failure (AMRF) syndrome can only be diagnosed using genetic test. Using

's as a form of diagnosis can prove difficult as patients differ in their neurophysiology. In Lafora's disease EEGs can show slowing background activity or focal discharges as well as epileptiform discharges. In ULD EEGs show generalized epileptiform discharges and in MERRF patients show background slowing. Therefore, diagnosis is best made using a combination of different tools like signs and symptoms, age of onset, EEG, gene testing, enzyme measurements, and

biopsy A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, an interventional radiologist, or an interventional cardiology, interventional cardiologist. The process involves the extraction of sampling (medicine), sample ...

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...

and

muscle Muscle is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to muscle contra ...

Differential diagnosis

The main component setting PME apart from other forms of

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

is progressive deterioration and resistance to treatment. Therefore, in the early stages of PME the symptoms and

may appear like

Generalized epilepsy Generalized epilepsy is a form of epilepsy characterized by generalized seizures that occur with no obvious cause. Generalized seizures, as opposed to focal seizures, are a type of seizure that manifests as impaired consciousness, bilateral moto ...

Juvenile myoclonic epilepsy Juvenile myoclonic epilepsy (JME), also known as Janz syndrome or impulsive petit mal, is a form of hereditary, idiopathic generalized epilepsy, representing 5–10% of all epilepsy cases. Typically it first presents between the ages of 12 and 18 ...

, benign childhood myoclonic epilepsy, and

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...

. It is crucial for ensure initial treatment is appropriate to measure how the condition progresses. Incorrect treatment can also result in wrong PME diagnosis.

Management

The is no cure for PME. Efforts are instead placed in managing the symptoms, specifically the

and

s as these can cause major harm to the individual. However, treating the symptoms with

can be difficult because PME individuals can become resistant. Some antiepileptic drugs used in treatment are

valproic acid Valproate (valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with ...

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

s, phehobarbital,

piracetam Piracetam is a drug that has efficacy in cognitive disorders, vertigo, cortical myoclonus, dyslexia, and sickle cell anemia; sources differ on its usefulness for dementia. Piracetam is sold as a medication in many European countries. Piracetam ...

zonisamide Zonisamide, sold under the brand name Zonegran among others, is a medication used to treat the symptoms of epilepsy and Parkinson's disease. Chemically it is a sulfonamide. It serves as an anticonvulsant used primarily as an adjunctive therapy ...

clonazepam Clonazepam, sold under the brand name Klonopin among others, is a benzodiazepine medication used to prevent and treat anxiety disorders, seizures, bipolar mania, agitation associated with psychosis, obsessive–compulsive disorder (OCD), and ...

, and

levetiracetam Levetiracetam, sold under the brand name Keppra among others, is a novel antiepileptic drug. (medication) used to treat epilepsy. It is used for Focal seizure, partial-onset, Myoclonic epilepsy, myoclonic, or tonic–clonic seizures, and is ta ...

. It is important to note that some antiepileptic drugs can worsen the symptoms, like

vigabatrin Vigabatrin, sold under the brand name Vigafyde among others, is a medication used in the management and treatment of Epileptic spasms, infantile spasms and refractory complex partial seizures. It works by inhibiting the catabolism, breakdown o ...

, carbamazepine, phenytoin, and

gabapentin Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat neuropathic pain and also for partial seizures of epilepsy. It is a commonly used medication for the treatment of neuropath ...

Clonazepam Clonazepam, sold under the brand name Klonopin among others, is a benzodiazepine medication used to prevent and treat anxiety disorders, seizures, bipolar mania, agitation associated with psychosis, obsessive–compulsive disorder (OCD), and ...

is currently the only drug approved by the

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

for monotherapy treatment of myoclonic seizures. Other treatments that have been used in PME patients are

deep brain stimulation Deep brain stimulation (DBS) is a type of neurostimulation therapy in which an implantable pulse generator is stereotactic surgery, surgically implanted subcutaneous tissue, below the skin of the chest and connected by Lead (electronics), leads ...

vagus nerve stimulation Vagus nerve stimulation (VNS) is a medical treatment that involves delivering electrical impulses to the vagus nerve. Initially developed by James Leonard Corning to compress or stimulate the carotid sheath, VNS typically refers to an implantable ...

, and diet but they have not been shown to improve seizures.

Prognosis

The prognosis of PME is ultimately dependent on the type of PME. In Lafora body disease the neurological deterioration progresses until resulting in a vegetative state and death within 10 years of diagnosis. Due to research and advances in antiepileptic medication, individuals with ULD can live up to 60 years of age. Nevertheless, severe myoclonus can lead to injury by falling and becoming reliant on a wheelchair.

Research

Because PME is so rare it is hard to do studies specifically double blind studies used to test different antiepileptic drugs. The wide range of symptoms including the differing EEG makes studying the effects of the AEDs difficult. In ULD,

oligonucleotide Oligonucleotides are short DNA or RNA molecules, oligomers, that have a wide range of applications in genetic testing, Recombinant DNA, research, and Forensic DNA, forensics. Commonly made in the laboratory by Oligonucleotide synthesis, solid-phase ...

therapeutic strategies have been used to replace gene effects while in

Sialidosis Mucolipidosis type I (ML I) is an inherited lysosomal storage disease that results from a deficiency of the enzyme alpha-N -acetyl neuraminidase (sialidase). The lack of this enzyme results in an abnormal accumulation of complex carbohydrates kno ...

replacement therapy has been studied in mouse models. In Lafora's disease

metformin Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome, ...

has been approved for treatment by the

European commission The European Commission (EC) is the primary Executive (government), executive arm of the European Union (EU). It operates as a cabinet government, with a number of European Commissioner, members of the Commission (directorial system, informall ...

. In MERRF bacterial proteins have been identified in treatment in

mitochondrial disease Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy o ...

s but further studies are needed.

History

The first instance where myoclonus and its relationship to epilepsy was in 1822 by Prichard. Lundborg was the first to name progressive myoclonus epilepsy in 1903 due to his study of several Swedish families as well as research done by Heinrich Unverricht in 1891. However, ULD was not recognized as a disease until a century later due to the rarity of the disease. In 1911, Lafora identified Lafora bodies but believed to be part of ULD. Lafora's genetics was not described until 1995.

Specific disorders

Several conditions can cause progressive myoclonic epilepsy. * Unverricht-Lundborg disease (Baltic myoclonus) * Myoclonus epilepsy and ragged red fibres (MERRF syndrome) *

Lafora disease Lafora disease is a rare, autosomal recessive genetic disorder which results in myoclonus epilepsy and usually results in death several years after the onset of symptoms. The disease is characterized by the accumulation of inclusion bodies, kno ...

* Neuronal ceroid lipofuscinoses *

* Dentatorubropallidoluysian atrophy (DRPLA) * Noninfantile neuronopathic form of

Gaucher disease Gaucher's disease or Gaucher disease () (GD) is a genetic disorder in which glucocerebroside (a sphingolipid, also known as glucosylceramide) accumulates in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low b ...

* Tetrahydrobiopterin deficiencies * Alpers disease * Juvenile Huntington disease * Niemann-Pick disease type C * North Sea progressive myoclonus epilepsy (NSPME)

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.

Phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anticonvulsant, anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence se ...

, 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 cystatin B (EPM1) 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 neurons and other body tissue. The generalized 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 acid Valproate (valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with ...

and

are first choice anticonvulsants, and the

ketogenic diet The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet, low-carbohydrate dietary therapy that in conventional medicine is used mainly to treat hard-to-control (refractory) epilepsy in children. The diet forces the body to b ...

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, encoded by the ''EPM2A'' gene, is a phosphatase, with a carbohydrate-binding domain, which is mutated in patients with Lafora disease. It contains a dual specificity phosphatase domain (DSP) and a carbohydrate binding module subtype 20 ...

. 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 (

lipofuscin Lipofuscin is the name given to fine yellow-brown pigment Granule (cell biology), granules composed of lipid-containing residues of Lysosome, lysosomal digestion. It is considered to be one of the aging or "wear-and-tear" pigments, found in the l ...

) 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-

neuraminidase Exo-α-sialidase (, sialidase, neuraminidase; systematic name acetylneuraminyl hydrolase) is a glycoside hydrolase that cleaves the glycosidic linkages of neuraminic acids: : Hydrolysis of α-(2→3)-, α-(2→6)-, α-(2→8)- glycosidic linkag ...

Myoclonic epilepsy and ataxia due to potassium (K+) channel mutation (MEAK)

MEAK is a form of progressive myoclonus epilepsy that typically begins between the ages of 3 and 15 years (the average of onset is 10 years). The first symptoms may include ataxia and myoclonus (unsteadiness and difficulty coordinating movements), along with generalized tonic-clonic ("grand mal") seizures. Individuals with MEAK typically do not experience developmental delays. The symptoms are progressive, and individuals with MEAK often need to use a wheelchair by their late teenage years because of movement difficulties and myoclonus. Many individuals with MEAK report temporary improvement of symptoms when they have a high fever. Seizures may become less frequent in adulthood, but other neurological complications, including myoclonus, ataxia and tremor, may worsen. Myoclonic epilepsy and ataxia due to potassium (K+) channel mutation (MEAK) is caused by a specific pathogenic variant ("mutation") in KCNC1 (G>A; p.Arg320His). KCNC1-related developmental and epileptic encephalopathy is associated with other pathogenic variants in KCNC1. In most individuals with KCNC1-related disorders, the pathogenic KCNC1 variant occurred spontaneously (de novo) and was not inherited from either parent.

Epidemiology

PME accounts for less than 1% of epilepsy cases at specialist centres. The incidence and

prevalence In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...

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.

References

External links

GeneReview/NCBI/NIH/UW entry on Progressive Myoclonus Epilepsy with Ataxia
{{DEFAULTSORT:Progressive Myoclonic Epilepsies Epilepsy types