By: Sofia Arreguin
DNM1 Genetic Mutation and Epilepsy
What is DNM1?
The DNM1 gene is responsible for encoding dynamin 1, a GTPase that is essential in a process known as synaptic vesicle endocytosis, in which particles floating outside the cell membrane are engulfed into the cell to be used or processed (Dhindsa et al., 2016). When engulfed, the membrane forms vesicles, or bubbles, that carry the particles further into the cell; the dynamin 1 protein works to sever these vesicles from the membrane. Essentially, neuronal communication occurs through neurotransmitters, which are released from a presynaptic neuron into the membrane of a postsynaptic neuron. Once released, the neurotransmitters are taken back into the presynaptic neuron, in a process known as reuptake, to be recycled, meaning they will be used again for another neuronal communication process. The protein dynamin 1 is an important factor in ensuring neurotransmitters are participating in reuptake. Once in the membrane, the neurotransmitters are placed into vesicles and, as mentioned, dynamin 1 works to separate the vesicle from the membrane (“Rare Diseases,” 2024). As a result, the synapses of the neurons are less cluttered with particles, preventing overstimulation and maintaining effective communication. This helps carry out neurotransmission, where neurotransmitters and particles work to send messages throughout the brain, supporting memory and learning, and allowing communication between neurons. However, genetic mutations in the DNM1 gene can disrupt these important processes, impairing brain development and leading to seizures.
DNM1-Related Epilepsy
Known by many names, such as Developmental and Epileptic Encephalopathy 31, DEE31, DNM1-related Epilepsy and Neurodevelopmental Disorder, or DNM1 Encephalopathy, this condition disrupts neuronal communication through its inability to properly recycle vesicle-containing neurotransmitters in the process of reuptake (“Rare Diseases,” 2024). If the neurotransmitters are unable to be taken back into the neuron, the synapse of the neuron becomes crowded and overstimulated, meaning it is being overexcited by the excessive excitatory signals, resulting in a seizure. Further, if there is no regulation in the reuptake of neurotransmitters, inhibitory neurotransmitters, like GABA, cannot enter the synapse to bind to a receptor; there is no route to combat the overexcitation of the neuron or the seizure. Different types of seizures can be seen with this condition, such as infantile spasms, which are seizures that occur in infants, tonic seizures, characterized by the stiffening of joints, focal seizures, affecting a specific area of the brain, absence seizures, characterized by blank stares, atonic seizures, which produce limp muscles, and generalized clonic-tonic seizures, where the limbs contract and tremble (“DNM1-encephalopathy,” n.d.). Other symptoms may include speech delay, motor delay, or an incapacity to walk and coordinate movement, low or increased muscle tone, blindness, rigidity in muscles, involuntary muscle contractions, macrocephaly or microcephaly, which are the development of a substantially sized head and a small-sized head, respectively, and regression in developmental milestones (“Rare Diseases,” 2024).
Considered to be an autosomal genetic disorder, DNM1 encephalopathy has 2 routes of reception: autosomal dominant and autosomal recessive. Through the autosomal dominant route, one copy of the gene is altered and determined to be a variant, which ultimately produces the disease or condition (“Rare Diseases,” 2024). This is generally considered to be de novo, meaning the gene or condition is occurring within the individual for the first time without inheritance from the parents. However, through the autosomal recessive route, the condition is inherited from both parents, as each contains 1 copy of the “disease-causing” gene mutation, though they themselves may be symptomless. Essentially, through autosomal dominant, only 1 copy of the gene needs to be altered for the disorder to appear, while autosomal recessive requires 2 variants within the gene.
In children, DNM1 usually contributes to the development of infantile spasms, which then later develops into an epilepsy syndrome named Lennox-Gastaut (LSG) (“DNM1-encephalopathy,” n.d.). Characterized as a prominent condition in children with a DNM1 mutation, Lennox-Gastaut is defined by its prevalence of seizures among children younger than age 4, as well as the several forms of seizures that manifest within them. They often have cluster seizures, meaning they experience multiple seizures in a short period of time. Seizure types include generalized tonic-clonic seizures, atonic seizures, tonic seizures, atypical absences, which involve blank stares, and myoclonic seizures, which include muscle jerks (“DNM1-encephalopathy,” n.d.). This condition is considered a severe form of epilepsy, as it injures the brain, producing brain damage and, therefore, the development of learning and developmental issues. Similar to the symptoms of DNM1 encephalopathy, LSG involves symptoms of regression, such as a loss of speech and the ability to walk, learning difficulties, as well as an inability to effectively control emotions or make friends (“LGS,” n.d.).
Treatments
Although there is no cure, as a result of its rarity and severity, there are methods and treatments that can be used to improve the quality of life of someone with DNM1 encephalopathy. To diagnose this disorder, medical professionals employ genetic testing, in which they assess the DNA of an individual to examine any abnormalities within the sequences of genes. Since there may be other diseases with similar symptoms, confirming the diagnosis of DNM1 encephalopathy is crucial to ensuring one receives the appropriate treatment to maintain an improved lifestyle. Other tools used for diagnosis include an electroencephalogram (EEG), which searches for unusual activity in the brain, such as seizures, and magnetic resonance imaging (MRI), which searches for structural changes in the brain (“DNM1-encephalopathy,” n.d.).
Such treatments, marketed as an effective therapy for those with DNM1 encephalopathy, stem from neurologists, who focus on neurological disorders, physical therapists, and speech pathologists. Recommended management for symptoms includes language therapy to help support a patient’s skill in speech, physical therapy to help in cases of low muscle tone, essentially rebuilding their strength, the prescription of glasses, and the administration of anti-seizure medications (ASMs) (“Rare Diseases,” 2024). The regulation of seizures is often stronger with the use of the medication, though the kind of medication would depend on the type of seizures a patient experiences. For example, the medication Clobazam would work well to control seizures in children with Lennox-Gastaut syndrome. Changing one’s diet to the ketogenic diet, which involves consuming low-carb, high-fat, and high-protein foods, is also recommended to regulate seizures. In cases where seizures are difficult to manage or are not responding well to medication, vagus nerve stimulation (VNS) is often advised, in which a device implanted into the brain produces electrical currents to the 10th cranial nerve, which is known as the vagus nerve (“LGS,” n.d.). It seems to be the preferred nerve to stimulate as it connects directly to the brain. The currents work to disrupt unusual activity in the brain; as the effect increases, the number and severity of seizures a patient experiences decreases (“LGS,” n.d.).
Conclusion
The mutation in the DNM1 gene disrupts the process by which the protein dynamin 1 engages in to help neurotransmitters enter back into the neuron. If such vesicles are unable to carry the neurotransmitters back into the membrane, the neurons would not be able to communicate with each other, slowing or inhibiting certain skills and abilities. As a result, the synapse of the neuron becomes overwhelmed by the high number of neurotransmitters present, often causing seizures to occur. Different types of seizures are associated with this disorder, and management of such seizures is possible. It is important that patients receive treatment to enjoy a better quality of life and to prevent further learning or neuronal complications in the brain. Further research into this condition is being conducted, and newer or more effective treatments and therapies may arise.
References
Dhindsa, R. S., Lowenstein, D. H., & Goldstein, D. B. (2016). Molecular Architecture and Neurobiology of the Epilepsies. Genomics, Circuits, and Pathways in Clinical Neuropsychiatry, 601–617. https://doi.org/10.1016/b978-0-12-800105-9.00037-8
DNM1-encephalopathy. (n.d.). Children’s Hospital of Philadelphia. https://www.chop.edu/conditions-diseases/dnm1-encephalopathy
Lennox-Gastaut Syndrome (LGS). (n.d.). Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/23171-lennox-gastaut-syndrome-lgs
Rare Diseases. (2024, August). National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/271477/
