What is DNM1-related epilepsy?

Pathogenic, or disease-causing, variants (“mutations”) in the DNM1 gene cause a neurodevelopmental disorder with a variety of features. People with DNM1-related disorder most often present with a spectrum of neurodevelopmental differences, including epileptic encephalopathies, most commonly with the presence of infantile spasms. Additionally, children with DNM1 tend to have developmental differences that can range from moderate to severe. Sometimes, children can present with developmental delay and intellectual disability without the presence of clinical seizures. The experience for every child with a DNM1-related disorder is different, and symptoms can vary.

Signs and symptoms of DNM1-related disorder

For children with DNM1-related disorder, developmental delays are often the first sign of the condition. Developmental delays can most often be observed during the first months to year of a child’s life, and these delays can range from moderate to profound. Seizures, most often infantile spasms, also are a common feature seen in children with DNM1-related disorder. Often, children experience infantile spasms within their first year of life, and then go on to develop an epilepsy condition called Lennox-Gastaut syndrome later in life. Even though seizures are seen in most people with DNM1-related disorder, there have been people who have presented with developmental differences or intellectual disability only and no seizures.

People with DNM1-related disorders can have different types of seizures, including:

• Infantile spasms
• Generalized tonic clonic seizures, also called grand mal seizures (in which the body, arms, and legs extend, then contract and shake)
• Absence seizures, or episodes consisting of staring
• Tonic (stiffening) seizures
• Focal seizures
• Atonic seizures

Other symptoms can include:

• Developmental delay and intellectual disability. Some people with DNM1-related disorder have a diagnosis of autism
• Hypotonia, or decreased muscle tone, which is seen in most people with DNM1-related disorder
• Hypertonia, or increased muscle tone
• Other movement disorders, like dystonia or non-epileptic myoclonus
• Microcephaly and cerebral atrophy
• Cortical visual impairment, or trouble seeing due to brain function, rather than from a problem with a person’s eye itself

Diagnosis of DNM1-related disorders

A diagnosis of DNM1-related disorder must be made through genetic testing. As there are many different genetic conditions that can cause developmental delays and seizures that begin in childhood, the only way that DNM1 disorder can be confirmed as a cause for these symptoms is through a genetic test.
Before or after a confirmed genetic diagnosis of DNM1, additional tests might be done including:

• Electroencephalogram (EEG), to look for evidence of abnormal brain activity and seizures
• Magnetic resonance imaging (MRI) to look for changes in brain structure

The majority of people with DNM1-related disorder have epilepsy. In addition to a DNM1 genetic diagnosis, often people will receive an epilepsy syndrome diagnosis that describes what a person’s seizures are like. For example, people with DNM1 can be diagnosed with:

• West Syndrome
• Lennox Gastaut syndrome

A person can have a diagnosis of DNM1-related disorder, which causes their seizures, but also have an epilepsy syndrome diagnosis. The epilepsy syndrome diagnosis is a clinical description of what seizure types a person experiences. For example, a person can have West Syndrome (infantile spasms) due to a disease-causing variant within the DNM1 gene.

Genetics of DNM1-related disorders

All children with a DNM1-related disorder have a pathogenic variant (“mutation”) in the gene DNM1, which encodes the instructions to make a protein in the brain that is essential to how brain cells communicate with one another. Pathogenic variants in the DNM1 gene lead to a change of function in a protein that allows brain cells to recycle vesicles. Brain cells must release messengers, called neurotransmitters, in order to communicate. Once the brain cell releases the messengers, the brain cell needs to recycle the container, or vesicle, that released the transmitters. The DNM1 protein is essential to helping the brain recycle the vesicles it needs to send these messages between cells. Changes in this process lead to the developmental differences and epilepsy seen in children with DNM1-related neurodevelopmental disorders.

In most children with DNM1-related disorders, the pathogenic DNM1 variant occurred spontaneously (de novo) and was not inherited from either parent. In rare cases, the pathogenic DNM1 variant has been passed on from an asymptomatic parent due to parental mosaicism. Just like a mosaic piece of art, in which each tile is different, a mosaic parent has distinct cell types. Most cells of a mosaic parent do not carry the pathogenic DNM1 variant. However, a small proportion of cells do carry the pathogenic DNM1 variant in very low levels that may be difficult or impossible to detect.

Treatment for DNM1-related disorders

Often, people with DNM1-related disorder have seizures that are difficult to manage and refractory to treatment with epilepsy therapies. Treatment of the seizures caused by DNM1-related disorders will vary based on seizure type and severity:

• A combination of antiseizure medications is typically used to control the different seizure types. The type of medication often depends on the specific epilepsy syndrome or type of seizures. No specific medication has been shown to be more effective than others in DNM1-related disorders.
• A different set of medications, known as “rescue therapies,” may be given to help stop or shorten clusters of seizures when they occur.
• Implantable devices such as vagus nerve stimulation (VNS) or responsive neurostimulation (RNS) may be considered when medications are not effective in controlling seizures.
• Dietary therapy, such as the ketogenic diet, may be helpful in some cases.

Family training and support is a key element in a successful epilepsy treatment plan. Parents and caregivers must know how to watch for and respond to seizures.

Cognitive and developmental delays or autism spectrum disorder associated with DNM1-related epilepsy are treated with physical, occupational and speech therapy, and with the support of early intervention services. Care may be provided by a developmental pediatrician.

Why choose CHOP for treatment of DNM1-related disorders?

Treatment of children with DNM1-related disorders and research into this genetic condition are a focus of members of the Epilepsy Neurogenetics Initiative (ENGIN). We are currently one of the largest centers worldwide to provide care for children with DNM1-related disorders. Families come to our ENGIN Clinic from all over the world. Children with DNM1-related disorders who are cared for at CHOP will receive cutting-edge genetic testing to confirm the underlying cause of their condition, as well as parental testing to confirm the diagnosis and inform recurrence risk with a subsequent pregnancy.

Through ENGIN, your child will have access to any other medical specialists they may need, as well as a full range of epilepsy therapies provided through CHOP’s Pediatric Epilepsy Program, including epilepsy management, dietary treatment and epilepsy surgery. They will also have access to cutting-edge research and clinical trials, as well as ongoing follow-up care.

All individuals seen in the ENGIN Clinic are offered the opportunity to participate in our research studies.

ENGIN integrates genetic testing into the diagnosis and treatment of children with difficult-to-treat or unexplained epilepsies, genetic epilepsy syndromes and other genetic neurodevelopmental disorders.

We combine cutting-edge clinical care and advanced genetic testing with innovative research to identify the underlying cause of a child’s epilepsy and develop an individualized approach to treatment and management.

Resources for DNM1-related disorders

• Ingo’s Epilepsy Genetics blog
• LGS foundation

References

Appenzeller, Silke, et al. "De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies." The American Journal of Human Genetics 95.4 (2014): 360-370.

Von Spiczak, Sarah and Helbig, KL, et al. "DNM1 encephalopathy: a new disease of vesicle fission." Neurology 89.4 (2017): 385-394.