Early Myoclonic Encephalopathy

What Causes Early Myoclonic Encephalopathy?

The exact cause of EME is unknown, but many different metabolic disorders, genetic conditions, and structural brain abnormalities have been associated with the disorder.

Potential causes of EME include:

• Zellweger syndrome
• Menke syndrome
• Nonketotic hyperglycinemia
• Pyridoxine and pyridoxal-5-phosphate disorders
• Methylmalonic acidemia
• Organic acid disorders and urea cycle disorders

In some cases, the underlying cause of EME is not identifiable.

Is Early Myoclonic Encephalopathy Hereditary?

Many of the conditions that can cause EME are inherited. In most cases, the disorder seems to be inherited in an autosomal recessive pattern. This means that a child must inherit two copies of the disorder-causing gene mutation, one from each parent, to develop the condition. A parent who carries only one copy of the mutation will usually show no symptoms but may pass the mutation to their children. Two parents, each carrying the mutation, have a 25 percent chance of having an affected child with each pregnancy. Fifty percent of their pregnancies will produce a carrier child. Twenty-five percent of the time, their child will not inherit a mutated gene, meaning they will not have the disorder or be able to pass on the mutation to their children.

How Is Early Myoclonic Encephalopathy Detected?

Signs of EME appear very early, sometimes within a few hours of birth. Seizures typically begin within the first ten days of delivery, and a diagnosis usually comes within the first three months.

How Is Early Myoclonic Encephalopathy Diagnosed?

To diagnose EME, a doctor will evaluate the baby’s symptoms and family history while ruling out other potential causes of the symptoms.

Diagnostic steps for EME usually include:

• Electroencephalogram (EEG) examination of electrical brain activity. This exam will look for a burst suppression pattern, in which spikes in brain activity are followed by periods of abnormally low levels of activity.
• Magnetic resonance imaging (MRI) exams to look for structural abnormalities in the brain that may be causing symptoms.
• Blood tests to look for metabolic and genetic disorders that may be the underlying cause of EME

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Early Myoclonic Encephalopathy Treated?

EME has no cure, and seizures are usually resistant to medications effective in controlling other types of epilepsy. Depending on the underlying cause of the disorder, treatment options may include:

• Anti-seizure medications such as clobazam, clonazepam, topiramate, zonisamide, phenobarbital, valproate, or felbamate
• Treatment for metabolic disorders when the cause is known
• Surgery, in cases where seizure activity occurs in one specific part of the brain
• Vagus nerve stimulation
• Ketogenic diet

How Does Early Myoclonic Encephalopathy Progress?

In most cases, children with EME do not survive past the age of two. Even when a baby with the disorder survives early childhood, the developmental complications of EME cause severe, life-long disabilities. Some children may be left in a persistent vegetative state, with no awareness of their surroundings.

In some cases, EME progresses into other forms of early childhood epilepsy, including West syndrome (infantile spasms) and Lennox-Gastaut Syndrome.

How Is Early Myoclonic Encephalopathy Prevented?

There is no known way to prevent EME. People who have a family history of the disorder or have had another child with the condition are advised to consult with a genetic counselor to assess their risk before having children.

Early Myoclonic Encephalopathy Caregiver Tips

• Educate yourself about EME. The disorder has many potential causes, and it uniquely affects each child. Learn all you can about the condition and your child’s specific experience with it so you can be an informed, effective part of the treatment process.
• Find support from people who know what you’re going through. The Epilepsy Foundation operates a 24/7 helpline through which you can find information and links to support resources.

Early Myoclonic Encephalopathy Brain Science

Some scientists have noted that several conditions associated with EME, including nonketotic hyperglycinemia, pyridoxine dependency, and pyridoxal-phosphate dependency, are also associated with high levels of the naturally occurring chemical glutamate in the bloodstream. In addition, the SLC25A22 gene, which has been associated with EME, is also involved in the function of glutamate within cells. These associations suggest that problems with glutamate levels may play a vital role in the development of EME.

Glutamate is a neurotransmitter, a chemical that helps to facilitate the transmission of electrical signals between nerve cells. The elevated levels of glutamate seen in these conditions may interfere with normal brain signal transmission, resulting in EME symptoms.

Early Myoclonic Encephalopathy Research

Title: Genetics of Severe Early Onset Epilepsies

Stage: Recruiting

Contact: Annapurna Poduri, MD, MPH

Boston Children’s Hospital

Boston, MA

Investigators at Boston Children’s Hospital are conducting research to better understand the genetic factors which may contribute to disorders related to epilepsy. These findings may help explain the broad spectrum of clinical characteristics and outcomes seen in people with epilepsy.

Many children with epilepsy experience seizures that respond well to treatment. However, a few types of epilepsy are characterized by seizures that begin very early in childhood and are associated with severe intellectual and/or developmental disabilities. These conditions, known as progressive epileptic encephalopathies, are particularly severe and are often difficult to treat. These syndromes include infantile spasms, early infantile epileptic encephalopathy with suppression bursts (Ohtahara syndrome), malignant migrating partial epilepsy of infancy, early myoclonic epileptic encephalopathy, and severe myoclonic epilepsy of infancy (Dravet syndrome).

The investigators’ current research effort is focused on children with epileptic encephalopathies, in particular Ohtahara syndrome. The investigators’ goal is to identify genetic alterations (known as “mutations”) that cause Ohtahara syndrome. By doing so, the investigators hope to improve the diagnosis and treatment for this condition. It is also possible that understanding the genetic basis of Ohtahara syndrome may, in some instances, make it possible to prevent it from occurring in the future.

Title: Creation of a Register of Patients With Neonatal-onset Epileptic Encephalopathy (IMPROVE)

Stage: Recruiting

Study director: Jean Olivier Arnaud  

Assistance Publique Hopitaux De Marseille

Marseille, France

Electrical activity emerges in the third trimester of pregnancy, plays an important role in constructing cortical maps, and is impaired in patients with severe early epileptic encephalopathies (EOEE). EOEE are rare and severe epileptic syndromes characterized by epilepsy that begins within the first three months of life and is associated with rapid deterioration of motor, cognitive and behavioral skills.

There is a genetic basis for the EOEE. Together with other laboratories, the investigators have identified de novo pathogenic variants in the KCNQ2 gene encoding the Kv7.2 subunit of the Kv7 / M potassium channel, a channel known to control neuronal excitability in the brain and spinal cord via the current M (IM). Pathogenic variants of the KCNQ2 gene represent the leading cause of EOEE, and the term KCNQ2-related epileptic encephalopathy (KCNQ2-REE) is now used to define this condition.

KCNQ2-REE patients have a remarkably homogeneous phenotype at the start, with epilepsy that begins in the first days after birth, seizures that result in tonic muscle spasms that last from 1 to 10 seconds, and an interictal EEG called “suppression-burst.” That is, paroxysmal bursts of activity interspersed with periods of electrical silence. In this group, more than 50% of the patients present remission of epilepsy and a quasi-normalization of the EEG, which can occur a few weeks to several months after the onset of the seizures. However, despite this positive evolution in terms of seizures, the developmental progression is abnormal. The phenotype is severe with an absence of language, autistic behavior, and subsequent development of motor disorders such as diplegia, spasticity, ataxia, or dystonia.

This project aims to increase knowledge of epileptic encephalopathies linked to KCNQ2 at the clinical and molecular levels, decipher the pathophysiological mechanisms, and propose therapeutic strategies.

This project aims to describe better the clinical, EEG, imaging, developmental, and long-term follow-up characteristics of patients carrying the KCNQ2 mutation identified in the laboratory.

Title: Memantine for Epileptic Encephalopathy

Stage: Recruiting

Principal investigator: Kenneth Myers, MD, PhD, FRCPC  

Children Hospital – MUHC

Montreal, Quebec

Memantine, a drug approved for Alzheimer’s dementia, exerts its therapeutic effect through its action as a low to moderate affinity non-competitive (open channel) N-methyl-D-aspartate receptor (NMDA-R) antagonist which binds preferentially to the NMDA receptor-operated cation channels. It blocks the effects of persistently elevated levels of glutamate that may lead to neuronal dysfunction. Memantine may also have anti-inflammatory effects. Memantine has been used off-label in children and adolescents with autism spectrum disorder to improve cognitive impairment.

Epileptic encephalopathy and other forms of epilepsy may occur due to multiple etiologies, including genetic and inflammatory pathologies. Ion channels were long considered to be implicated in genetic epilepsy. Indeed one of the many possible causes of epilepsy is NMDA receptor dysfunction.

In the present study, the investigators plan to investigate the potential benefit of memantine as a treatment for epileptic encephalopathy. A double-blind placebo-controlled cross-over design will be used, with participants receiving six weeks of memantine and six weeks of placebo, with a 2-week washout period in between.