Progressive myoclonus epilepsy

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Progressive myoclonus epilepsy [1]
Specialty Neurology

Progressive Myoclonic Epilepsies (PME) are a rare group of inherited neurodegenerative diseases characterized by myoclonus, resistance to treatment, and neurological deterioration. [2] The cause of PME depends largely on the type of PME. Most PMEs are caused by autosomal dominant or recessive and mitochondrial mutations. [2] The location of the mutation also affects the inheritance and treatment of PME. Diagnosing PME is difficult due to their genetic heterogeneity and the lack of a genetic mutation identified in some patients. [3] 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 seizures through antiepileptic medication (AED). [3] [2]

Contents

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. [2]

Symptoms often include action or stimuli induced myoclonus, seizures, neuropathy, cognitive decline, and spike and wave or no cerebral discharges. [4] 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. [4] [3]

Signs and symptoms

The most common symptom of PME is myoclonus. [2] The myoclonus can be fragmented or multifocal and can be triggered by posture, actions, and external stimuli such as light, sound, and touch. [2] The type of myoclonus differs between the types of PME. Other symptoms of PME include generalized, tonic clonic, tonic, and atypical absence seizures. [4] In Lafora's disease the seizures are occipital and the person experiences transient blindness as well as visual hallucinations. [4] [5] 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. [4] [5]

As PME progresses neurological ability decreases and can lead to myopathy, neuropathy, cognitive decline, cerebellar ataxia, and dementia. [4] [2] 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 and therapy but diagnosis of specific PME depends on genetic testing, EEG (electroencephalography), enzyme measurements and more. [4] [2] [3]

Diagnosis

Diagnosis of PME is based on the individual's signs and symptoms as well as failure to respond to antiepileptic drugs and therapy. [3] Further diagnosis support includes EEG results, genetic testing, enzyme testing, and skin and muscle biopsies. [2] Gaucher's disease can be diagnosed through enzyme testing as it is a metabolic disease. [4] Lafora's disease can be diagnosed using skin biopsies. [4] While Action myoclonus renal failure (AMRF) syndrome can only be diagnosed using genetic test. [4] Using EEG'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. [3] In ULD EEGs show generalized epileptiform discharges and in MERRF patients show background slowing. [2] 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 of skin and muscle. [4]

Differential diagnosis

The main component setting PME apart from other forms of epilepsy is progressive deterioration and resistance to treatment. [2] Therefore, in the early stages of PME the symptoms and EEG may appear like Generalized epilepsy, Juvenile myoclonic epilepsy, benign childhood myoclonic epilepsy, and Huntington's disease. [3] It is crucial for ensure initial treatment is appropriate to measure how the condition progresses. Incorrect treatment can also result in wrong PME diagnosis. [2] [3]

Management

The is no cure for PME. Efforts are instead placed in managing the symptoms, specifically the myoclonus and seizures as these can cause major harm to the individual. [2] However, treating the symptoms with antiepileptic drugs can be difficult because PME individuals can become resistant. Some antiepileptic drugs used in treatment are valproic acid, benzodiazepines, phehobarbita l, piracetam, zonisamide, clonazepam, and levetiracetam. It is important to note that some antiepileptic drugs can worsen the symptoms, like vigabatrin, carbamazepine, phenytoin, and gabapentin. [2] [3] Clonazepam is currently the only drug approved by the FDA for monotherapy treatment of myoclonic seizures. [3] Other treatments that have been used in PME patients are deep brain stimulation, vagus nerve stimulation , and diet but they have not been shown to improve seizures. [2] [3]

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. [4] Due to research and advances in antiepileptic medication, individuals with ULD can live up to 60 years of age. [2] Nevertheless, severe myoclonus can lead to injury by falling and becoming reliant on a wheelchair. [2]

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. [4]  In ULD, oligonucleotide therapeutic strategies have been used to replace gene effects while in Sialidosis enzyme replacement therapy has been studied in mouse models. [6] In Lafora's disease metformin has been approved for treatment by the European commission. [6] In MERRF bacterial proteins have been identified in treatment in mitochondrial diseases but further studies are needed. [6]

History

The first instance where myoclonus and its relationship to epilepsy was in 1822 by Prichard. [7] 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. [7] However, ULD was not recognized as a disease until a century later due to the rarity of the disease. [7] In 1911, Lafora identified Lafora bodies but believed to be part of ULD. Lafora's genetics was not described until 1995. [7]

Specific disorders

Several conditions can cause progressive myoclonic epilepsy.

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, 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. [9]

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 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.

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) 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.

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 (c. 959G>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.[ citation needed ] The incidence 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. [10]

See also

Related Research Articles

Lafora disease is a rare, adult-onset and 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, known as Lafora bodies, within the cytoplasm of the cells in the heart, liver, muscle, and skin. Lafora disease is also a neurodegenerative disease that causes impairment in the development of brain (cerebral) cortical neurons and is a glycogen metabolism disorder.

Absence seizures are one of several kinds of generalized seizures. In the past, absence epilepsy was referred to as "pyknolepsy," a term derived from the Greek word "pyknos," signifying "extremely frequent" or "grouped". These seizures are sometimes referred to as petit mal seizures ; however, usage of this terminology is no longer recommended. Absence seizures are characterized by a brief loss and return of consciousness, generally not followed by a period of lethargy. Absence seizures are most common in children. They affect both sides of the brain.

<span class="mw-page-title-main">Myoclonus</span> Involuntary, irregular muscle twitch

Myoclonus is a brief, involuntary, irregular twitching of a muscle, a joint, or a group of muscles, different from clonus, which is rhythmic or regular. Myoclonus describes a medical sign and, generally, is not a diagnosis of a disease. It belongs to the hyperkinetic movement disorders, among tremor and chorea for example. These myoclonic twitches, jerks, or seizures are usually caused by sudden muscle contractions or brief lapses of contraction. The most common circumstance under which they occur is while falling asleep. Myoclonic jerks occur in healthy people and are experienced occasionally by everyone. However, when they appear with more persistence and become more widespread they can be a sign of various neurological disorders. Hiccups are a kind of myoclonic jerk specifically affecting the diaphragm. When a spasm is caused by another person it is known as a provoked spasm. Shuddering attacks in babies fall in this category.

<span class="mw-page-title-main">MELAS syndrome</span> Medical condition

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the family of mitochondrial diseases, which also include MIDD, MERRF syndrome, and Leber's hereditary optic neuropathy. It was first characterized under this name in 1984. A feature of these diseases is that they are caused by defects in the mitochondrial genome which is inherited purely from the female parent. The most common MELAS mutation is mitochondrial mutation, mtDNA, referred to as m.3243A>G.

Myoclonic epilepsy refers to a family of epilepsies that present with myoclonus. When myoclonic jerks are occasionally associated with abnormal brain wave activity, it can be categorized as myoclonic seizure. If the abnormal brain wave activity is persistent and results from ongoing seizures, then a diagnosis of myoclonic epilepsy may be considered.

<span class="mw-page-title-main">MERRF syndrome</span> Medical condition

MERRF syndrome is a mitochondrial disease. It is extremely rare, and has varying degrees of expressivity owing to heteroplasmy. MERRF syndrome affects different parts of the body, particularly the muscles and nervous system. The signs and symptoms of this disorder appear at an early age, generally childhood or adolescence. The causes of MERRF syndrome are difficult to determine, but because it is a mitochondrial disorder, it can be caused by the mutation of nuclear DNA or mitochondrial DNA. The classification of this disease varies from patient to patient, since many individuals do not fall into one specific disease category. The primary features displayed on a person with MERRF include myoclonus, seizures, cerebellar ataxia, myopathy, and ragged red fibers (RRF) on muscle biopsy, leading to the disease's name. Secondary features include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity, or multiple lipomata. Mitochondrial disorders, including MERRFS, may present at any age.

Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy (SMEI), is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or fever. It is very difficult to treat with anticonvulsant medications. It often begins before one year of age, with six months being the age that seizures, char­ac­ter­ized by prolonged convulsions and triggered by fever, usually begin.

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 with myoclonic seizures. These events typically occur after awakening from sleep, during the evening or when sleep-deprived. JME is also characterized by generalized tonic–clonic seizures, and a minority of patients have absence seizures. It was first described by Théodore Herpin in 1857. Understanding of the genetics of JME has been rapidly evolving since the 1990s, and over 20 chromosomal loci and multiple genes have been identified. Given the genetic and clinical heterogeneity of JME some authors have suggested that it should be thought of as a spectrum disorder.

Unverricht–Lundborg disease is the most common form of an uncommon group of genetic epilepsy disorders called the progressive myoclonus epilepsies. 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 1901 and 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.

Ramsay Hunt syndrome type 1 is a rare, degenerative, neurological disorder characterized by myoclonus epilepsy, intention tremor, progressive ataxia and occasionally cognitive impairment

Ohtahara syndrome (OS), also known as early infantile epileptic encephalopathy (EIEE) is a progressive epileptic encephalopathy. The syndrome is outwardly characterized by tonic spasms and partial seizures within the first few months of life, and receives its more elaborate name from the pattern of burst activity on an electroencephalogram (EEG). It is an extremely debilitating progressive neurological disorder, involving intractable seizures and severe intellectual disabilities. No single cause has been identified, although in many cases structural brain damage is present.

Mitochondrially encoded tRNA phenylalanine also known as MT-TF is a transfer RNA which in humans is encoded by the mitochondrial MT-TF gene.

Mitochondrially encoded tRNA lysine also known as MT-TK is a transfer RNA which in humans is encoded by the mitochondrial MT-TK gene.

Myoclonic astatic epilepsy (MAE), also known as myoclonic atonic epilepsy or Doose syndrome, is a generalized idiopathic epilepsy. It is characterized by the development of myoclonic seizures and/or myoclonic astatic seizures. Some of the common monogenic causes include mutations in the genes SLC6A1 (3p25.3),CHD2 (15q26.1), AP2M1 (10q23.2).

Jeavons syndrome is a type of epilepsy. It is one of the most distinctive reflex syndromes of idiopathic generalized epilepsy characterized by the triad of eyelid myoclonia with and without absences, eye-closure-induced seizures, EEG paroxysms, or both, and photosensitivity. Eyelid myoclonia with or without absences is a form of epileptic seizure manifesting with myoclonic jerks of the eyelids with or without a brief absence. These are mainly precipitated by closing of the eyes and lights. Eyelid myoclonia is the defining seizure type of Jeavons syndrome.

<span class="mw-page-title-main">Spinal muscular atrophy with progressive myoclonic epilepsy</span> Rare neurodegenerative disease whose symptoms include slowly progressive muscle wasting

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), sometimes called Jankovic–Rivera syndrome, is a very rare neurodegenerative disease whose symptoms include slowly progressive muscle (atrophy), predominantly affecting proximal muscles, combined with denervation and myoclonic seizures. Only 12 known human families are described in scientific literature to have SMA-PME.

An epilepsy syndrome is defined as "a characteristic cluster of clinical and EEG features, often supported by specific etiological findings ."

PRICKLE1-related progressive myoclonus epilepsy with ataxia is a very rare genetic disorder which is characterized by myoclonic epilepsy and ataxia.

GOSR2-related progressive myoclonus ataxia, also known as Progressive myoclonic epilepsy type 6 is a rare genetic type of progressive myoclonus ataxia which is characterized by progressive myoclonic epilepsy with an early onset which is associated with generalized tonic-clonic seizures, petit mal seizures, and drop attacks, variable degrees of scoliosis, areflexia, high levels of creatine kinase serum, and late-onset cognitive decline.

SLC13A5 citrate transporter disorder, or SLC13A5 Epilepsy, is a rare genetic spectrum disorder that presents with neurological symptoms. Symptoms include severe seizures, ataxia, dystonia, teeth hypoplasia, poor communication skills, difficulty standing or walking, as well as developmental delay. Other names associated with SLC13A5 Epilepsy include SLC13A5 Citrate Transporter Disorder, Citrate Transporter Disorder, SLC13A5 Deficiency, Early Infantile Epilepsy Encephalopathy 25 (EIEE25), Developmental Epilepsy Encephalopathy 25 (DEE25), and Kohlschutter-Tonz Syndrome (non-ROGDI).

References

  1. ↑ Berg AT, Berkovic SF, Brodie MJ, et al. (April 2010). "Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009". Epilepsia. 51 (4): 676–85. doi: 10.1111/j.1528-1167.2010.02522.x . PMID   20196795.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Shahwan, Amre; Farrell, Michael; Delanty, Norman (April 2005). "Progressive myoclonic epilepsies: a review of genetic and therapeutic aspects". The Lancet Neurology. 4 (4): 239–248. doi:10.1016/s1474-4422(05)70043-0. ISSN   1474-4422. PMID   15778103. S2CID   2304164.
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  5. 1 2 Delgado-Escueta, A.V.; Ganesh, Subramaniam; Yamakawa, Kazuhiro (2001). "Advances in the Genetics of Progressive Myoclonus Epilepsy". American Journal of Medical Genetics. 106 (2): 129–138. doi:10.1002/ajmg.1575. PMID   11579433 – via AJMG.
  6. 1 2 3 Orsini, Alessandro; Valetto, Angelo; Bertini, Veronica; Esposito, Mariagrazia; Carli, Niccolò; Minassian, Berge A.; Bonuccelli, Alice; Peroni, Diego; Michelucci, Roberto; Striano, Pasquale (October 2019). "The best evidence for progressive myoclonic epilepsy: A pathway to precision therapy". Seizure. 71: 247–257. doi:10.1016/j.seizure.2019.08.012. ISSN   1059-1311. PMC   7288863 . PMID   31476531.
  7. 1 2 3 4 Genton, Pierre; Striano, Pasquale; Minassian, Berge A. (2016). "The history of progressive myoclonus epilepsies". Epileptic Disord. 18 (S2): S3–S10. doi:10.1684/epd.2016.0834. PMC   5777179 . PMID   27621064 – via Pudmed.
  8. ↑ Wirrell, Elaine (2016). "Infantile, Childhood, and Adolescent Epilepsies". CONTINUUM: Lifelong Learning in Neurology. 22 (1, Epilepsy): 60–93. doi:10.1212/con.0000000000000269. PMID   26844731. S2CID   19104641.
  9. ↑ Genton, P. (2006). "[Unverricht-Lundborg disease (PME1)]". Rev. Neurol. (Paris) (in French). 162 (8–9): 819–26. doi:10.1016/S0035-3787(06)75084-6. PMID   17028542.
  10. ↑ "Unverricht-Lundborg Disease" . Retrieved 2008-01-26.
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