A generalized type of seizure characterized by a sudden loss of muscle tone is a(n):

Myoclonic Atonic Epilepsy

NORD gratefully acknowledges Bailey Perczak, NORD Editorial Intern from the University of Notre Dame and Eric H. Kossoff, MD, Professor of Neurology and Pediatrics, Johns Hopkins University School of Medicine, for the preparation of this report.

Synonyms of Myoclonic Atonic Epilepsy

• Doose syndrome
• epilepsy with myoclonic-astatic seizures
• epilepsy with myoclonic-atonic seizures (EMAS)
• epilepsy with myoclonic-astatic crisis
• myoclonic astatic epilepsy
• MAE

General Discussion

Summary

Myoclonic atonic epilepsy (MAE) is a rare childhood epilepsy syndrome characterized by myoclonic-atonic seizures, which are typically recognized as jerking muscle contractions followed by sudden muscle limpness. While the disorder is characterized by the presence of myoclonic-atonic seizures in particular, individuals often experience other seizure types as well. This earns MAE the classification of a generalized seizure disorder, and it is also considered to be part of the GEFS+ (genetic epilepsy with febrile seizures plus) spectrum. There is believed to be a strong genetic component to the condition, and males are affected at a rate nearly three times higher than females, but no specific gene has ever been identified for MAE. Onset of the disorder typically occurs between the ages of 7 months and 6 years. Many of these children will have normal development until the time that their seizures begin. Diagnosis can include clinical evaluation and EEG (electroencephalogram) readings to detect abnormal brain waves. Results may be normal at the onset of the disorder but patients with continued seizures typically have abnormal EEG findings. Various medications and dietary changes can be prescribed to control the seizure activity. Ketogenic diet therapy is the most helpful therapy in most children. Between 60-80% of MAE patients achieve seizure remission, whether through medical treatment or adherence to dietary regimens, but those whose seizures persist may be at risk for more intractable (hard to control) seizures and intellectual disabilities.

Introduction

Myoclonic atonic epilepsy, or Doose syndrome, as it was first named, was coined in 1970 by Dr. Hermann Doose. The disorder was initially recognized as being a separate entity from generalized tonic-clonic seizures (characterized by a loss of consciousness followed by convulsive muscle contractions) and Lennox-Gastaut syndrome (including tonic, atonic, myoclonic, and atypical absence seizures). Patients with MAE were set apart from these other disorders based on a combination of key differences, including:

– Normal childhood development prior to seizure onset
– Age of onset between 2 and 5
– Presence of drop attacks, which are associated with myoclonic-atonic seizures and occur as sudden losses of muscle tone that lead to falls
– Abnormal EEG (electroencephalogram) readings

Signs & Symptoms

MAE is a seizure disorder that begins in early childhood. Nearly all patients have their first seizures before the age of five, with 24% beginning before the child’s first birthday. Most children with MAE have normal development up to the time of diagnosis, though 20% have minor delays that often present with speech difficulties. For most patients, the first seizure is a generalized tonic-clonic seizure. “Tonic” refers to a stiffening stage, wherein the body becomes rigid. This can cause falls and loss of bladder control due to the inability to control muscle function. The tonic period usually lasts for less than thirty seconds before transitioning into the “clonic” phase, which involves the limb jerks and rapid movements that are characteristically associated with epileptic episodes. Throughout the duration of the episode, the child is completely unconscious and unaware of what is occurring, and may not regain consciousness until a few minutes afterwards.

Although generalized tonic-clonic seizures are the most common onset type, approximately 22% of MAE patients present with absence seizures, and up to 9% are shown to have myoclonic-atonic seizures in their first epileptic episode. Children whose seizures begin after the age of four are more likely to experience absence seizures as their presenting type.

A few days or weeks after their initial seizure, patients begin to experience frequent myoclonic jerks or myoclonic-atonic “drop” seizures. The term “myoclonic” describes a sudden convulsion and rapid movement of muscle groups. Myoclonic jerks are brief contractions of the head, shoulders, or arms, and in some children, the entire body, though these still differ from myoclonic seizures. The individual will not be conscious throughout the episode, but because it occurs so rapidly, it may appear as if they are fully aware. The experience can be relatively mild, appearing only as a head nod or unintentional twitch, or can cause movement of the entire body, leading to falls. By contrast, while myoclonic-atonic seizures also have this characteristic increase in muscle stiffness, they are then followed by an atonic period. The atonic phase results in a sudden loss of muscle tone. This causes the child to immediately fall to the ground, and has been often described as “like someone cutting the strings on a marionette puppet”. Myoclonic-atonic seizures are very rare, are a key diagnostic feature of the disorder. They have also been referred to as atonic attacks or “drop attacks”, and never occur in series. Both myoclonic and myoclonic-atonic seizures typically increase in frequency following their onset. At the peak of seizure activity, 48% of families report 10 to 50 seizures per day.

Absence seizures can also be common in children with MAE. These episodes may be difficult to recognize and may appear as if the child is only daydreaming. These seizures can occur multiple times per day and usually last between 15 and 30 seconds. In some children, the only visible indication is a slight head nod motion or facial twitches. The child may have a blank gaze and will not respond to any type of stimulus. However, as soon as the period ends, the child will be fully conscious.

Atypical absence seizures are similar to normal absence episodes, but may have rare attributes that push them out of the typical classification. Many patients will have the blank stare associated with absence seizures but may be partially responsive. There also may be distinct motor behaviors, including involuntary motions, clonic jerking movements or tonic stiffening spells. Oftentimes, the child will have delayed reactions or seem confused, agitated or out of typical character.

The last seizure classification that is commonly associated with MAE is non-convulsive status epilepticus. The term “status epilepticus” is used to describe seizures that persist for an abnormally extended period of time. This can be the result of one epileptic episode lasting far beyond the typical time span, or when several seizures occur in succession. Convulsive status epilepticus shares symptoms with tonic clonic seizures, and is incredibly rare among MAE patients. By contrast, non-convulsive status epilepticus manifests similarly to absence episodes. They are not particularly life-threatening and typically do not result in brain damage, but can be disruptive to the child’s memory and level of functioning. In some children, these periods can persist for hours to days if intervention does not occur. The individual will not be fully aware of their surroundings during these episodes, and some have likened it to a disoriented, dizzy sensation. Throughout this time, the child will be unresponsive and immobile, and may drool or have slurred speech. An inability to swallow during this time can prevent water and medications from being consumed, which can lead to the individual needing to be brought to the hospital. There have also been incidences of “high functioning” non-convulsive status epilepticus, in which the child is capable of some degree of autonomy and action.

Along with these different classified seizures, there are other symptoms that can be experienced by patients with MAE, including:

● Ataxia, which typically presents as unsteady walking or difficulty with coordinated movements. This occurs in over 80% of patients.
● Cognitive impairment, ranging from normal cognition to severe impairment and autistic features, depending on seizure activity and prescribed medications.
● Attention deficit hyperactivity disorder (ADHD) and attention deficit disorder (ADD), which are experienced by 15-20% of patients.
● Behavioral disturbances, which have been anecdotally reported to increase in response to changes in medication dosage or administration.

Causes

The exact cause of MAE is unknown. Between 34-44% of patients have at least one family member with a history of epilepsy. Interestingly, the type of prior seizure disorder is not consistent among family members, but typically remains within the GEFS+ (genetic epilepsy with febrile seizures plus) spectrum. The GEFS+ family of seizures are characterized by seizures that are typically brought on by febrile or afebrile (non-fever induced) seizures and are recurrent. These cases must be seen among several family members throughout different generations in order to be classified as GEFS+ cases. The most frequent seizure types among those with GEFS+ include myoclonic, atonic, and absence seizures.

Some mutations have been identified by researchers and appear to occur in a percentage of MAE cases. These mutations have been observed both in patients who inherited them from their parents and from those whose mutations seem to have arisen de novo (randomly) without any heritable pattern. Around 14% of patients are found to have monogenic (single gene) mutations. These alterations are not present in all patients, and some individuals develop the disorder without any familial history or genetic findings.

Mutations in the following genes have been found in patients with myoclonic atonic epilepsy:

– SLC6A1 (More frequently reported and is associated with increased levels of
severe intellectual disability, speech disorders and movement impairments. Codes for a major GABA transporter found in the central nervous system. GABA is an amino acid that blocks or slows nerve signals in the brain- plays a role in reducing anxiety, fear and stress)
– SLC2A1 (Found in a variety of brain disorders and correlates with speech, movement, and intellectual impairments, along with decreased head size. Is known to result in a GLUT1 transporter deficiency, which impairs the body’s ability to transport glucose to the brain through the blood-brain barrier.)
– SCN1A (sodium channel neuronal type 1 alpha subunit mutation)
– SCN1B (sodium channel neuronal type 1 beta subunit mutation)
– SCN2A (sodium channel neuronal type 2 alpha subunit mutation)
– GABRG2 (gamma-aminobutyric acid receptor subunit gamma-2 mutation)
– CHD2 (Correlated with high levels of intellectual disability and photosensitive (light-sensitive) seizures. Is a mutation of the chromodomain helicase DNA-binding protein 2)
– SYNGAP1
– NEXMIF
– AP2M1
– KIAA2022

Children diagnosed with mutations in these genes often experience a more severe form of MAE or may present with more developmental delays prior to the onset of the seizures. It has been suggested that patients with SLC2A1 mutations may experience MAE as an additional rare side effect due to the GLUT1 deficiency, indicating that the MAE symptoms are not the cause of their symptoms, but are a byproduct of a larger disorder. The GLUT1 transporters that are lacking due to a SLC2A1 mutation are cellular components that are responsible for bringing glucose from the bloodstream into the brain. When these transporters are lacking, it can prevent the brain from receiving adequate amounts of glucose, which is an important energy source. A similar hypothesis has been proposed with SLC6A1 mutations, which are believed to cause severe developmental delay long before seizure onset. The experience of MAE with this mutation is similarly believed to be a side effect of the neurological abnormalities.

Affected Populations

Myoclonic atonic epilepsy is a rare disorder that accounts for 1-2% of all epilepsy diagnoses. This translates to affecting less than 1 in every 100,000 children born each year. When the disorder presents before the first year of life, males are affected far more than females, in about a 3:1 ratio. However, when diagnosed after the first year of life, the gender ratio becomes nearly equal. One in four children experiences their onset seizure before their first birthday, and 94% of cases occur before the age of five. In one third of cases, the child has family members with a history of some form of epilepsy, typically within the GEFS+ (genetic epilepsies with febrile seizures plus) spectrum. Around 2% of children have family histories of myoclonic and atonic seizures specifically. While this may seem like a small percentage, it is 200 times greater than the correlation found among the general population.

Diagnosis

While there isn’t a genetic diagnosis for myoclonic atonic epilepsy, a combination of clinical symptoms and EEG findings are used for diagnosis. While patients with MAE may experience a variety of seizure types, the presence of myoclonic-atonic seizures is absolutely indicative of MAE. Additional findings typically include:

– Neurotypical child development until onset of seizures, though mild developmental delay may be present in some
– Onset before 5 years of age in 94% of cases
– Presentation of generalized tonic-clonic seizures in 60% of cases
– Normal blood tests and MRI (magnetic resonance imaging) brain scans
– Spike and wave or polyspike and wave EEG patterns (abnormal EEG patterns); initial EEG can be normal in many children.

Since some of the genetic mutations associated with MAE are treatable with medication and diet, genetic sequencing for mutations such as SLC2A1 may be beneficial. A deficiency in GLUT1 transporters caused by these mutations can also be diagnosed through lumbar puncture to detect abnormal glucose levels in the spinal fluid.

Standard Therapies

Treatment

Treatment success for myoclonic atonic epilepsy is highly variable. The spectrum of outcomes ranges from complete remission with normal intellect to persistent medication-resistant seizures that result in severe developmental disability. Around 68% of patients experience seizure remission. In total, around 60% have normal intellectual development, 20% experience mild delay and 20% have moderate to severe intellectual delay.

The first line of approach for treating MAE often includes anti-seizure medications (ASM). The medications that are typically prescribed include:

– sodium valproate (Epilim, Depakote)
– topiramate (Topamax)
– lamotrigine (Lamictal)
– clobazam (Onfi, Frisium)
– ethosuximide (Zarontin)
– zonisamide (Zonegran)
– levetiracetam (Keppra)

Around 25% of myoclonic atonic epilepsy patients are responsive to these medication approaches. The second-line approach that is usually taken when there is resistance to 1-2 anti-seizure medications involves the ketogenic diet. This requires a consumption of high amounts of fat, moderate proportions of protein and minimal servings of carbohydrates. This forces the body to use the consumed fat for energy, instead of the typical carbohydrate source. The ketogenic diet has been shown to be surprisingly successful and reduces seizures by over 50% in 80-90% of patients. Many experts in the field believe it the treatment of choice and should be tried as soon as the diagnosis is made. It is particularly beneficial for those who also have the SLC2A1 mutations and can cause significant reduction in the severity of intellectual impairment and seizure frequency.

It is important to note that some anti-seizure medications have been shown to increase the seizure frequency in patients with myoclonic atonic epilepsy. Vigabatrin and sodium channel blockers such as carbamazepine and phenytoin are among these treatments that are not effective for MAE. Lamotrigine, listed above as a possible treatment, is also not recommended for those who experience myoclonic seizures as their primary seizure type.

There are also individuals that are treated with short spans of steroids (e.g., prednisolone), typically across 2-4 weeks. This approach is most commonly taken when the child is experiencing multiple myoclonic-atonic or myoclonic seizures each day, but must be monitored carefully. When steroids are used over longer periods of time, there can be significant side-effects, and seizure remission may occur when the steroids are discontinued. In extreme cases, there is a surgical option of corpus callosotomy (the severing of the connective tissue that joins the two cerebral hemispheres). However, this approach has only been taken in rare circumstances when the patient is experiencing multiple daily drop attacks that are non-responsive to medication and dietary approaches.

It has been suggested that later diagnosis and increased frequencies of generalized tonic-clonic seizures are associated with poorer clinical outcomes. Patients with non-convulsive status epilepticus are also shown to have increased rates of cognitive impairment.

There are other approaches that are recommended for management of symptoms and behavioral disturbances. Occupational therapy (OT) is used to teach fine motor skills and use of everyday tools and is recommended for children that may be having difficulties in school or around the household. Physical therapy (PT) helps to strengthen large motor movements, reduce pain and improve overall function. Since speech difficulties are common among MAE patients, speech therapy may be helpful for improving communication skills.

Investigational Therapies

NORD Member Organizations

• SLC6A1 Connect
  • USA
  • Phone: (303) 907-8038
  • Email: [email protected]
  • Website: https://slc6a1connect.org/

Other Organizations

• Epilepsy Foundation
  • 8301 Professional Place
  • Landover, MD 20785-7223
  • Phone: (866) 330-2718
  • Toll-free: (800) 332-1000
  • Email: [email protected]
  • Website: http://www.epilepsyfoundation.org
• Genetic and Rare Diseases (GARD) Information Center
  • PO Box 8126
  • Gaithersburg, MD 20898-8126
  • Phone: (301) 251-4925
  • Toll-free: (888) 205-2311
  • Website: http://rarediseases.info.nih.gov/GARD/

References

JOURNAL ARTICLES

Köhler S, et al. The human phenotype ontology in 2021. Nucleic Acids Research. 2021;49, D1, 8 January 2021, Pages D1207–D1217. https://doi.org/10.1093/nar/gkaa1043

Nickels K, Kossoff EH, Eschbach K, Joshi C. Epilepsy with myoclonic atonic seizures (Doose syndrome): Clarification of diagnosis and treatment options through a large multi-center cohort. Epilepsia. 2021;62(1):120-127. https://pubmed.ncbi.nlm.nih.gov/33190223/

Kelley SA, and Kossoff EH. Doose syndrome (myoclonic–astatic epilepsy): 40 years of progress. Developmental Medicine and Child Neurology. 2020. https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-8749.2010.03744.x.

Tang S, et al. Phenotypic and genetic spectrum of epilepsy with myoclonic atonic aeizures. Epilepsia. 2020; 27 Mar.https://slc6a1connect.org/wp-content/uploads/2020/06/Phenotypic-and-genetic-spectrum-of-epilepsy-with-myoclonic-atonic-seizures.pdf.

Wei Z, et al. Treatment of myoclonic-atonic epilepsy caused by SLC2A1 de novo mutation with ketogenic diet. Medicine. 2019;98:18 (e15428). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504322/pdf/medi-98-e15428.pdf.

Nickels K, Thibert R, Rau S, et al. How do we diagnose and treat epilepsy with myoclonic-astatic seizures (Doose syndrome)? Results of the Pediatric Epilepsy Research Consortium Survey. Epilepsy Res. 2018;144:14-19. https://pubmed.ncbi.nlm.nih.gov/29729532/

Larsen J, et al. The role of slc2a1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of glut1 deficiency syndrome. Epilepsia. 2015; 56(12):e203–e208.https://onlinelibrary.wiley.com/doi/pdf/10.1111/epi.13222

Trivisano M, et al. CHD2 mutations are a rare cause of generalized epilepsy with myoclonic–atonic seizures. Epilepsy & Behavior. 2015; 7 Aug. https://pubmed.ncbi.nlm.nih.gov/26262932

Thomas RH, Zhang LM, Carvill GL, et al. CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures. Neurology. 2015; vol. 84,9: 951-8. https://pubmed.ncbi.nlm.nih.gov/25672921/

Carvill GL, McMahon JM, Schneider A, et al. Mutations in the gaba transporter slc6a1 cause epilepsy with myoclonic-atonic seizures. AJHG. 2015 96, 5, 7 May:808-815. https://www.sciencedirect.com/science/article/pii/S0002929715000695

Roth FC and Draguhn A. GABA metabolism and transport: effects on synaptic efficacy. Neural Plasticity. 2012. https://www.hindawi.com/journals/np/2012/805830

Tang S and Pal DK. Dissecting the genetic basis of myoclonic‐astatic epilepsy. Epilepsia. 2012; 53(8):1303–1313. https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1528-1167.2012.03581.x.

Trivisano M, et al. Myoclonic astatic epilepsy: an age-dependent epileptic syndrome with favorable seizure outcome but variable cognitive evolution. Epilepsy Research. 2011; Nov;97(1-2):133-41. https://pubmed.ncbi.nlm.nih.gov/21873030/

Mullen SA, Marini C, Suls A, et al. Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Arch Neurol. 2011;68(9):1152–1155. https://pubmed.ncbi.nlm.nih.gov/21555602/

Kilaru S and Bergqvist AGC. Current treatment of myoclonic astatic epilepsy: clinical experience at the Children’s Hospital of Philadelphia. Epilepsia. 2007; 48(9):1703–1707 https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1528-1167.2007.01186.x.

Stephani U. The natural history of myoclonic astatic epilepsy (DOOSE syndrome) and Lennox‐Gastaut syndrome. Epilepsia. 2006; 47(Suppl. 2):53–55. https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1528-1167.2006.00690.x

Gayatri NA, and Livingston JH. Aggravation of epilepsy by anti‐epileptic drugs. Developmental Medicine and Child Neurology. 2006; 48: 394–398. https://onlinelibrary.wiley.com/doi/epdf/10.1017/S0012162206000843.

Nabbout R., et al. Absence of mutations in major Gefs+ genes in myoclonic astatic epilepsy. Epilepsy Research. 2003;56:127-133. https://www.sciencedirect.com/science/article/pii/S0920121103001530.

Dulac O. Epileptic encephalopathy. Epilepsia 2001;42 Suppl 3 23-6. doi:10.1046/j.1528-1157.2001.042suppl.3023.x/.

Kaminska A, et al. Delineation of cryptogenic Lennox-Gastaut syndrome and myoclonic astatic epilepsy using multiple correspondence analysis Epilepsy.1999. https://pubmed.ncbi.nlm.nih.gov/10463847/

INTERNET

Myoclonic Astatic Epilepsy. Orphanet. April 2021. https://www.orpha.net/consor/www/cgi-bin/OC_Exp.php?lng=EN&Expert=1942 Accessed Feb 14, 2022.

Helbig I. The Genetics of Doose Syndrome or Myoclonic Astatic Epilepsy. Beyond the Ion Channel. 25 June 2020. http://epilepsygenetics.net/2020/06/25/the-genetics-of-doose-syndrome-or-myoclonic-astatic-epilepsy/ Accessed Feb 14, 2022.

Myoclonic Atonic Epilepsy. OMIM. 15 June 2015. https://omim.org/entry/616421. Accessed Feb 14, 2022.

Epilepsy with Myoclonic-Atonic Seizures. International League Against Epilepsy. March 2020. https://www.epilepsydiagnosis.org/syndrome/epilepsy-myoclonic-atonic-overview.html. Accessed Feb 14, 2022.

Appleton R. Myoclonic Astatic Epilepsy (Doose Syndrome). Epilepsy Action, Dec. 2019. https://www.epilepsy.org.uk/info/syndromes/myoclonic-astatic-epilepsy-doose-syndrome. Accessed Feb 14, 2022.

Hernandez A, and Wirrell E. Myoclonic Atonic Epilepsy (Doose syndrome). Epilepsy Foundation. Nov. 2019. https://www.epilepsy.com/learn/types-epilepsy-syndromes/myoclonic-atonic-epilepsy-doose-syndrome Accessed Feb 14, 2022.

Epilepsy with Myoclonic-Atonic Seizures. Genetic and Rare Diseases Information Center. Last updated: 7/25/2018. https://rarediseases.info.nih.gov/diseases/2169/epilepsy-with-myoclonic-atonic-seizures Accessed Feb 14, 2022.

What Is Doose Syndrome? Doose Syndrome Epilepsy Alliance. https://doosesyndrome.org/. Accessed Feb 14, 2022.

The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.

The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.

National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100

What are the 4 types of generalized seizures?

What is a generalized atonic seizure?

What type of seizure affect the muscles?

What is the difference between grand mal and petit seizures?