Clinical Assessments and EEG Analyses of Encephalopathies Associated With Dynamin-1 Mutation

Li, Hua; Fang, Fang; Xu, Manting; Liu, Zhimei; Zhou, Jianli; Wang, Xiaohui; Wang, Xiaofei; Tong, Haizhou

doi:10.3389/fphar.2019.01454

Cited by 13 publications

(19 citation statements)

References 25 publications

(23 reference statements)

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“…11 Since then, over 30 individuals with heterozygous, mostly de novo DNM1 variants were reported. [11][12][13][14][15][16][17][18] All except for one reported variant, a de novo in-frame 6 bp insertion, are missense variants affecting highly conserved residues and predicted to exert a dominant-negative effect on dynamin-1 function. 19 The mutational spectrum of DNM1 includes several recurrent variants.…”

Section: Introductionmentioning

confidence: 99%

Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state

et al. 2021

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BackgroundDevelopmental and epileptic encephalopathies (DEEs) represent a group of severe neurological disorders characterised by an onset of refractory seizures during infancy or early childhood accompanied by psychomotor developmental delay or regression. DEEs are genetically heterogeneous with, to date, more than 80 different genetic subtypes including DEE31 caused by heterozygous missense variants in DNM1.MethodsWe performed a detailed clinical characterisation of two unrelated patients with DEE and used whole-exome sequencing to identify causative variants in these individuals. The identified variants were tested for cosegregation in the respective families.ResultsWe excluded pathogenic variants in known, DEE-associated genes. We identified homozygous nonsense variants, c.97C>T; p.(Gln33*) in family 1 and c.850C>T; p.(Gln284*) in family 2, in the DNM1 gene, indicating that biallelic, loss-of-function pathogenic variants in DNM1 cause DEE.ConclusionOur finding that homozygous, loss-of-function variants in DNM1 cause DEE expands the spectrum of pathogenic variants in DNM1. All parents who were heterozygous carriers of the identified loss-of-function variants were healthy and did not show any clinical symptoms, indicating that the type of mutation in DNM1 determines the pattern of inheritance.

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Section: Introductionmentioning

confidence: 99%

Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state

et al. 2021

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“…All patients presented with severe/profound ID, in many cases (17/30) associated with the absence of verbal communication ( 100 , 106 , 107 , 109 ). Also, two-thirds of the cases (22/30) showed deep axial and/or diffuse hypotonia and severe involvement of motor skills ( 100 , 106 – 109 , 111 , 112 ).…”

Section: Dnm1mentioning

confidence: 99%

Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction

et al. 2022

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The proper connection between the pre- and post-synaptic nervous cells depends on any element constituting the synapse: the pre- and post-synaptic membranes, the synaptic cleft, and the surrounding glial cells and extracellular matrix. An alteration of the mechanisms regulating the physiological synergy among these synaptic components is defined as “synaptopathy.” Mutations in the genes encoding for proteins involved in neuronal transmission are associated with several neuropsychiatric disorders, but only some of them are associated with Developmental and Epileptic Encephalopathies (DEEs). These conditions include a heterogeneous group of epilepsy syndromes associated with cognitive disturbances/intellectual disability, autistic features, and movement disorders. This review aims to elucidate the pathogenesis of these conditions, focusing on mechanisms affecting the neuronal pre-synaptic terminal and its role in the onset of DEEs, including potential therapeutic approaches.

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“… 1 , 2 , 3 , 4 Individuals with pathogenic DNM1 variants suffer from two of the most severe developmental and epileptic encephalopathy (DEE) syndromes, Lennox-Gastaut syndrome and infantile spasms, with at least 20 heterozygous de novo variants identified in 33 patients predominantly in the critical GTPase and the middle domains of the protein. 5 , 6 , 7 , 8 , 9 , 10 The identification of affected individuals is likely to increase as DNM1 is now included on screening panels for severe childhood epilepsy. Children with DNM1 mutations suffer from intractable conditions manifesting as early-onset seizures, global developmental delay, profound intellectual disability, lack of speech, muscular hypotonia, dystonia, and spasticity.…”

Section: Introductionmentioning

confidence: 99%

RNAi-Based Gene Therapy Rescues Developmental and Epileptic Encephalopathy in a Genetic Mouse Model

et al. 2020

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Developmental and epileptic encephalopathy (DEE) associated with de novo variants in the gene encoding dynamin-1 ( DNM1 ) is a severe debilitating disease with no pharmacological remedy. Like most genetic DEEs, the majority of DNM1 patients suffer from therapy-resistant seizures and comorbidities such as intellectual disability, developmental delay, and hypotonia. We tested RNAi gene therapy in the Dnm1 fitful mouse model of DEE using a Dnm1 -targeted therapeutic microRNA delivered by a self-complementary adeno-associated virus vector. Untreated or control-injected fitful mice have growth delay, severe ataxia, and lethal tonic-clonic seizures by 3 weeks of age. These major impairments are mitigated following a single treatment in newborn mice, along with key underlying cellular features including gliosis, cell death, and aberrant neuronal metabolic activity typically associated with recurrent seizures. Our results underscore the potential for RNAi gene therapy to treat DNM1 disease and other genetic DEEs where treatment would require inhibition of the pathogenic gene product.

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Clinical Assessments and EEG Analyses of Encephalopathies Associated With Dynamin-1 Mutation

Cited by 13 publications

References 25 publications

Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state

Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state

Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction

RNAi-Based Gene Therapy Rescues Developmental and Epileptic Encephalopathy in a Genetic Mouse Model

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