Dynamin-1 Related Epilepsy

Seeking innovative cures for children with Dynamin-1 Developmental Epileptic Encephalopathy (DEE), ultra rare disease

Dynamin-1 Related Epilepsy

Seeking innovative cures for children with Dynamin-1 Developmental Epileptic Encephalopathy (DEE), ultra rare disease

DYNAMIN-1 related epilepsy explained

DNM1-related developmental and epileptic encephalopathy is rare and the prevalence is unknown, however it is thought to make up an important portion of all developmental and epileptic encephalopathies (DEEs). DEEs refer to a group of severe epilepsy-related disorders that typically emerge in early childhood. These conditions are characterized by recurrent seizures (abnormal brain activity) and can interfere with normal brain function, often causing developmental delays or impairments.

Genotype-phenotype correlation

The expression and severity of the disorder depend on the location of the pathogenic variants with variants in the G domain and the middle domain being associated to a more severe phenotype than those in the PH domain or GED.

For developmental and epileptic encephalopathy 31A, autosomal dominant (MIM:616346)

Caused by a specific type of genetic change where one copy of the gene has a harmful alteration. These changes are usually new (not inherited) and have a very low recurrence risk for siblings (less than 1%).

These pathogenic variants are missense or in-frame insertions or indels with dominant negative effects on protein function. This means that the mutant protein impairs the correct functioning of the normal (WT) protein.

NM_004408.4(DNM1):c.709C>T p.(Arg237Trp) is a common recurrent variant that has been reported in approximately a third of affected individuals.

Role of dynamin 1 (the protein generated by DNM1)

Dynamin 1 plays a crucial role in all types of synaptic vesicle endocytosis. It is recruited to the neck of budding synaptic vesicles, where it undergoes self-assembly and facilitates membrane fission by harnessing the mechanical force generated through GTP hydrolysis.

This protein consists of several distinct domains, each with specific functions. The GTPase domain (G domain) is responsible for hydrolyzing guanosine triphosphate (GTP), while the bundle signaling element (BSE) ensures proper protein folding. Dimerization occurs via the stalk region, and the PH domain enables binding to phosphoinositides. Additionally, the GTPase effector domain (GED) regulates GTPase activity, and the proline-rich domain (PRD) facilitates interactions with Src homology 3 (SH3) domains of other synaptic proteins (as reviewed by Ferguson and De Camilli, 2012).

Functional studies of pathogenic variants in DNM1 suggest that the disease pathogenesis may be due to impaired synaptic vesicle endocytosis through either impaired GTP hydrolysis, impaired self-assembly or absent gene product.

Author: Dr. Katherine Bonnycastle

Symptoms

Symptoms of DNM1-related DEE usually appear in infancy

In almost all individuals with pathogenic variants in DNM1:

Seizures usually starting with infantile spasms, evolving to Lennox-Gastaut syndrome and progressing to include focal seizures, generalized seizures, absence seizures, atonic seizures, tonic seizures, generalized tonic-clonic seizures, myoclonic seizures

Abnormal EEG

Severe global developmental delay

Severe psychomotor delay

Severe-profound intellectual disability

Generalized or axial hypotonia

Non-verbal

Non-ambulatory

Brain MRI usually normal, but may show cerebral atrophy

May also be present:

Autism spectrum disorder

Stereotypies

Limb shaking

Ataxia

Dystonia

Spasticity

Microcephaly

Brain MRI usually normal

Widely spaced teeth

Abnormal myelination

Less frequent:

Mesial temporal sclerosis

Hypomyelinating leukoencephalopathy and ventriculomegaly

Watch Dynamin membrane constriction

dynamin-1 in action

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Welcome to DNM1 EPILEPSY

Dynamin 1 explained

Patients & Care givers

Dynamin 1 is a protein encoded by the DNM1 gene. Dynamin-1 is a GTPASE that consists of 864 amino acids and plays a crucial role in synaptic neurotransmitter vesicle recycling. It is primarily expressed in the brain, where mutations can have significant and severe implications.

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