DNM1 gene pathogenic variation in 3 cases with early infantile epileptic encephalopathy-31 and Literature review_Journal of Epilepsy

Authors：

LU Xiaodong ¹ , CHEN Zhichun ² ,  ZHOU Yuanfeng ¹ , QIU Tian ¹ , WANG Xinhua ¹ , WANG Ji ¹ , CAI Yiming ¹ , ZHOU Shuizhen ¹ , WANG Yi ¹ , WU Bingbing ³

1. Department of Neurology, Children’s Hospital of Fudan University, Shanghai, 201102, China;
2. Department of Neurology, Children’s Hospital of Fudan University, Xiamen Branch, Xiamen, 361000, China;
3. The Molecular Genetic Diagnosis Center, Shanghai Key Lab of Birth Defects, Pediatrics Research Institute, Children’s Hospital of Fudan University, Shanghai, 201102, China;

Corresponding author：

ZHOU Yuanfeng, Email: yuanfengzhou99@163.com

Keywords：

DNM1; Epileptic encephalopathy; Hypotonia; Intellectual and movement disability; Epileptic spasm

DOI：

10.7507/2096-0247.20210018

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Objective To explore the clinical, genetic and prognostic features of early infantile epileptic encephalopathy caused by DNM1 gene pathogenic variations.Methods Clinical phenotype, genotype and prognosis of 3 individuals with de novo variants in DNM1 gene were analyzed retrospectively. Through using “Dynamin-1” or “DNM1” as key words to search literature at database of China National Knowledge Infrastructure, Wanfang, PubMed and OMIM. Genotype-phenotype correlations were analyzed by analysis of variance (ANOVA).Result Among the 3 patients, 1 female and 2 males. 2 cases with epileptic spasm and 1 case with focal clonic seizure or secondary generalized tonic-clonic seizure were manifested with onset age from 2 to 17 months. De novo variants at NM_004408.4: c.415 G>A(P. Gly 139Arg) in 2 inviduals and NM_004408.4: c.545 C>A(P. Ala 182Asp)in 1 invidual of DNM1 gene were identified by gene testing. After follow-up at age of 2~3 years, all patients were presented with hypotonia, severe intellectual disability, non-verbal, non-ambulatory, drug-resistant epilepsy and feeding difficulties. 36 cases with pathogenic DNM1 variants were reported by far, totally 39 cases were included. Of the 39 patients, hypotonia were found to be independent of the locus of genetic variants, while those inviduals with variants in the GTPase and middle domains almost presented severe or profound intellectual disability and epilepsy. 31 patients diagnosed with epilepsy and complete clinical data were further analyzed, epileptic spasm was the most common types of seizure. Absent seizure was significantly more common in those patients with variants in the GTPase domains (P=0.02), compared to those patients with variants in the middle domains. No statistical differences were found in gender, onset age, other types of seizure and drug treatment response between variants in the GTPase and middle domains.Conclusion Hypotonia, early onset epilepsy, severe intellectual and movement disability were the common features in patients with DMN1 related encephalopathy. Epileptic spasm was the most common types of seizure, no significant differences were found in the phenotype between the GTPase and middle domains expect for absent seizure. Our patients also presented with feeding difficulties.

Citation： LU Xiaodong, CHEN Zhichun, ZHOU Yuanfeng, QIU Tian, WANG Xinhua, WANG Ji, CAI Yiming, ZHOU Shuizhen, WANG Yi, WU Bingbing. DNM1 gene pathogenic variation in 3 cases with early infantile epileptic encephalopathy-31 and Literature review. Journal of Epilepsy, 2021, 7(2): 104-111. doi: 10.7507/2096-0247.20210018 Copy

1.	王秋菊, 沈亦平, 陈少科, 等. 遗传变异分类标准与指南. 中国科学: 生命科学, 2017, 47(6): 668-688.
2.	Sahly AN, Krochmalnek E, St-Onge J, et al. Severe DNM1 encephalopathy with dysmyelination due to recurrent splice site pathogenic variant. Hum Genet, 2020, 139(12): 1575-1578.
3.	Li H, Fang F, Xu M, et al. Clinical assessments and EEG analyses of encephalopathies associated with Dynamin-1 mutation. Front Pharmacol, 2019, 4(10): 1454.
4.	Kolnikova M, Skopkova M, Ilencikova D, et al. DNM1 encephalopathy - atypical phenotype with hypomyelination due to a novel de novo variant in the DNM1 gene. Seizure, 2018, 56: 31-33.
5.	Brereton E, Fassi E, Araujo GC, et al. Mutations in the PH Domain of DNM1 are associated with a nonepileptic phenotype characterized by developmental delay and neurobehavioral abnormalities. Mol Genet Genomic Med, 2018, 6(2): 294-300.
6.	Rim JH, Kim SH, Hwang IS, et al. Efficient strategy for the molecular diagnosis of intractable early-onset epilepsy using targeted gene sequencing. BMC Med Genomics, 2018, 11(1): 6.
7.	Lazzara A, Asghar S, Zacharia T, et al. DNM1 Mutation in a child associated with progressive bilateral mesial temporal sclerosis. Clin Case Rep, 2018, 6(11): 2037-2039.
8.	von Spiczak S, Helbig KL, Shinde DN, et al. DNM1 encephalopathy: A new disease of vesicle fission. Neurology, 2017, 89(4): 385-394.
9.	Fung CW, Kwong AK, et al. Gene panel analysis for nonsyndromic cryptogenic neonatal/infantile epileptic encephalopathy. Epilepsia Open, 2017, 2(2): 236-243.
10.	Allen NM, Conroy J, Shahwan A, et al. Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion. Epilepsia, 2016, 57(1): e12-e17.
11.	Nakashima, M, Kouga, T, Lourenco, et al. De novo DNM1 mutations in two cases of epileptic encephalopathy. Epilepsia, 2016, 57(1): e18-23.
12.	邓小鹿, 尹飞, 张慈柳, 等. Dynamin-1 基因新生突变导致婴儿痉挛症一例并文献复习. 中华儿科杂志, 2016, 54(11): 856-859.
13.	EuroEPINOMICS-RES Consortium; Epilepsy Phenome/Genome Project; Epi4K Consortium. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet, 2014, 95(4): 360-370.
14.	McCabe MP, Shore AN, et al. Altered fast synaptic transmission in a mouse model of DNM1-associated developmental epileptic encephalopathy. eNeuro, 17: ENEURO. 0269-20.2020.
15.	Dhindsa RS, Bradrick SS, Yao X, et al. Epileptic encephalopathy-causing mutations in DNM1 impair synaptic vesicle endocytosis. Neurol Genet, 2015, 1(1): e4.
16.	Lee A, Frank DW, Marks MS, et al. Dominant-negative inhibition of receptor-mediated endocytosis by a dynamin-1 mutant with a defective pleckstrin homology domain. Curr Biol, 1999, 9(5): 261-264.

1. 王秋菊, 沈亦平, 陈少科, 等. 遗传变异分类标准与指南. 中国科学: 生命科学, 2017, 47(6): 668-688.
2. Sahly AN, Krochmalnek E, St-Onge J, et al. Severe DNM1 encephalopathy with dysmyelination due to recurrent splice site pathogenic variant. Hum Genet, 2020, 139(12): 1575-1578.
3. Li H, Fang F, Xu M, et al. Clinical assessments and EEG analyses of encephalopathies associated with Dynamin-1 mutation. Front Pharmacol, 2019, 4(10): 1454.
4. Kolnikova M, Skopkova M, Ilencikova D, et al. DNM1 encephalopathy - atypical phenotype with hypomyelination due to a novel de novo variant in the DNM1 gene. Seizure, 2018, 56: 31-33.
5. Brereton E, Fassi E, Araujo GC, et al. Mutations in the PH Domain of DNM1 are associated with a nonepileptic phenotype characterized by developmental delay and neurobehavioral abnormalities. Mol Genet Genomic Med, 2018, 6(2): 294-300.
6. Rim JH, Kim SH, Hwang IS, et al. Efficient strategy for the molecular diagnosis of intractable early-onset epilepsy using targeted gene sequencing. BMC Med Genomics, 2018, 11(1): 6.
7. Lazzara A, Asghar S, Zacharia T, et al. DNM1 Mutation in a child associated with progressive bilateral mesial temporal sclerosis. Clin Case Rep, 2018, 6(11): 2037-2039.
8. von Spiczak S, Helbig KL, Shinde DN, et al. DNM1 encephalopathy: A new disease of vesicle fission. Neurology, 2017, 89(4): 385-394.
9. Fung CW, Kwong AK, et al. Gene panel analysis for nonsyndromic cryptogenic neonatal/infantile epileptic encephalopathy. Epilepsia Open, 2017, 2(2): 236-243.
10. Allen NM, Conroy J, Shahwan A, et al. Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion. Epilepsia, 2016, 57(1): e12-e17.
11. Nakashima, M, Kouga, T, Lourenco, et al. De novo DNM1 mutations in two cases of epileptic encephalopathy. Epilepsia, 2016, 57(1): e18-23.
12. 邓小鹿, 尹飞, 张慈柳, 等. Dynamin-1 基因新生突变导致婴儿痉挛症一例并文献复习. 中华儿科杂志, 2016, 54(11): 856-859.
13. EuroEPINOMICS-RES Consortium; Epilepsy Phenome/Genome Project; Epi4K Consortium. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet, 2014, 95(4): 360-370.
14. McCabe MP, Shore AN, et al. Altered fast synaptic transmission in a mouse model of DNM1-associated developmental epileptic encephalopathy. eNeuro, 17: ENEURO. 0269-20.2020.
15. Dhindsa RS, Bradrick SS, Yao X, et al. Epileptic encephalopathy-causing mutations in DNM1 impair synaptic vesicle endocytosis. Neurol Genet, 2015, 1(1): e4.
16. Lee A, Frank DW, Marks MS, et al. Dominant-negative inhibition of receptor-mediated endocytosis by a dynamin-1 mutant with a defective pleckstrin homology domain. Curr Biol, 1999, 9(5): 261-264.

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