Clinical features and genotype-phenotype correlations in epilepsy patients with de novo DYNC1H1 variants

被引：1

作者：

Cuccurullo, Claudia ^{[1
,2
]}

Irelli, Emanuele Cerulli ^{[3
]}

Ugga, Lorenzo ^{[4
]}

Riva, Antonella ^{[5
,6
]}

D'Amico, Alessandra ^{[7
]}

Cabet, Sara ^{[8
]}

Lesca, Gaetan ^{[9
,10
]}

Bilo, Leonilda ^{[1
]}

Zara, Federico ^{[5
,6
]}

Iliescu, Catrinel ^{[11
]}

Barca, Diana ^{[12
,13
]}

Fung, France ^{[14
,15
]}

Helbig, Katherine ^{[14
,15
]}

Ortiz-Gonzalez, Xilma ^{[14
,15
]}

Schelhaas, Helenius J. ^{[16
]}

Willemsen, Marjolein H. ^{[17
]}

van der Linden, Inge ^{[16
]}

Canafoglia, Laura ^{[18
,41
]}

Courage, Carolina ^{[19
,20
]}

Gommaraschi, Samuele ^{[20
]}

Gonzalez-Alegre, Pedro ^{[21
]}

Bardakjian, Tanya ^{[21
]}

Syrbe, Steffen ^{[22
]}

Schuler, Elisabeth ^{[22
]}

Lemke, Johannes R. ^{[23
]}

Vari, Stella ^{[24
]}

Roende, Gitte ^{[25
]}

Bak, Mads ^{[26
]}

Huq, Mahbulul ^{[27
]}

Powis, Zoe ^{[28
]}

Johannesen, Katrine M. ^{[29
]}

Hammer, Trine Bjorg ^{[29
]}

Moller, Rikke S. ^{[29
]}

Rabin, Rachel ^{[30
]}

Pappas, John ^{[30
]}

Zupanc, Mary L. ^{[31
]}

Zadeh, Neda ^{[32
,33
]}

Cohen, Julie ^{[34
]}

Naidu, Sakkubai ^{[35
]}

Krey, Ilona ^{[36
]}

Saneto, Russell ^{[37
,38
]}

Thies, Jenny ^{[39
]}

Licchetta, Laura ^{[40
]}

Tinuper, Paolo ^{[40
,41
]}

Bisulli, Francesca ^{[40
,41
]}

Minardi, Raffaella ^{[42
]}

Bayat, Allan ^{[29
,43
]}

Villeneuve, Nathalie ^{[44
]}

Molinari, Florence ^{[45
]}

Dafsari, Hormos Salimi ^{[46
,47
,48
,49
,50
,51
,52
]}

机构：

[1] Federico II Univ Naples, Epilepsy Ctr, Dept Neurosci Reprod & Odontostomatol Sci, Naples, Italy

[2] Osped Mare Hosp, Neurol & Stroke Unit, Naples, Italy

[3] Sapienza Univ Rome, Dept Human Neurosci, Rome, Italy

[4] Univ Federico II, Dept Adv Biomed Sci, Naples, Italy

[5] Univ Genoa, Dept Neurosci Rehabil Ophthalmol Genet Maternal &, Genoa, Italy

[6] Istituti Ricovero & Cura Carattere Sci Ist Giannin, Med Genet Unit, Genoa, Italy

[7] Tortorella Private Hosp, Dept Radiol, Salerno, Italy

[8] Hosp Civils Lyon, Hop Femme Mere Enfant, Pediat & Fetal Imaging, Lyon, France

[9] Hosp Civils Lyon, Serv Genet, Bron, France

[10] Univ Claude Bernard Lyon 1, Inst NeuroMyoGene, CNRS UMR5310, INSERM U1217, Lyon, France

[11] Carol Davila Univ Med & Pharm, Dept Clin Neurosci, Bucharest, Romania

[12] Prof Dr Alex Obregia Clin Hosp, Expertise Ctr Rare Dis Pediat Neurol, Dept Pediat Neurol, Bucharest, Romania

[13] Prof Dr Alex Obregia Clin Hosp, EpiCARE European Reference Network, Bucharest, Romania

[14] Childrens Hosp Philadelphia, Dept Pediat & Neurol, Philadelphia, PA USA

[15] Univ Penn, Sch Med, Philadelphia, PA USA

[16] Epilepsy Ctr Kempenhaeghe, Dept Neurol, Heeze, Netherlands

[17] Radboud Univ Nijmegen Med Ctr, Dept Human Genet, Nijmegen, Netherlands

[18] Fdn IRCCS Ist Neurol Carlo Besta, Integrated Diagnost Epilepsy, Milan, Italy

[19] Folkhalsan Res Ctr, Helsinki, Finland

[20] Univ Milan, Dept Biomed & Clin Sci, Milan, Italy

[21] Univ Penn, Perelman Sch Med, Dept Neurol, Philadelphia, PA USA

[22] Univ Hosp Heidelberg, Ctr Pediat & Adolescent Med, Div Pediat Epileptol, Heidelberg, Germany

[23] Univ Leipzig, Med Ctr, Ctr Rare Dis, Leipzig, Germany

[24] Univ Genoa, Pediat Neurol & Muscular Dis Unit, G Gaslini Inst, Dept Maternal & Child Hlth, Genoa, Italy

[25] Univ Hosp, Dept Pediat & Adolescent Med, Rigshosp, Copenhagen, Denmark

[26] Copenhagen Univ Hosp, Dept Clin Genet, Rigshosp, Copenhagen, Denmark

[27] Wayne State Univ, Dept Pediat, Detroit, MI USA

[28] Ambry Genet, Dept Emerging Genet Med, CGC 15 Argonaut, Aliso Viejo, CA USA

[29] Danish Epilepsy Ctr, Dept Epilepsy Genet & Personalized Med, Dianalund, Denmark

[30] NYU Grossman Sch Med, Dept Pediat, Clin Genet Serv, New York, NY USA

[31] Childrens Hlth Orange Cty, Orange, CA USA

[32] Childrens Hosp Orange Cty, Genet Ctr, Orange, CA USA

[33] Childrens Hosp Orange Cty, Div Med Genet, Orange, CA USA

[34] Johns Hopkins Univ, Sch Med, Kennedy Krieger Inst, Dept Neurol, Baltimore, MD USA

[35] Kennedy Krieger Inst, Dept Neurogenet, Baltimore, MD USA

[36] Univ Leipzig, Med Ctr, Inst Human Genet, Leipzig, Germany

[37] Univ Washington, Seattle Childrens Hosp, Dept Neurol, Seattle, WA USA

[38] Univ Washington, Seattle Childrens Hosp, Dept Pediat, Seattle, WA USA

[39] Univ Washington, Seattle Childrens Res Inst, Seattle, WA USA

[40] Ist Sci Neurol Bologna, IRCCS, Bologna, Italy

[41] EpiCARE European Reference Network, Bologna, Italy

[42] Univ Bologna, Dept Biomed & Neuromotor Sci, Bologna, Italy

[43] Univ Southern Denmark, Dept Reg Hlth Res, Odense, Denmark

[44] Timone Children Hosp, Pediat Neurol Dept, Marseille, France

[45] Politecn Torino, Dept Elect & Telecommun, Biolab, PolitoBIOMedLab, Turin, Italy

[46] Univ Cologne, Fac Med, Dept Pediat, Cologne, Germany

[47] Univ Hosp Cologne, Cologne, Germany

[48] Univ Cologne, Ctr Mol Med Cologne, Cologne, Germany

[49] Max Planck Inst Biol Ageing, Cologne, Germany

[50] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respons, Cologne, Germany

来源：

EPILEPSIA | 2024年 / 65卷 / 09期

关键词：

dynein; infantile epileptic spasms syndrome; lissencephaly/pachygyria; MCDs; DYNC1H1-related epilepsy; SPINAL MUSCULAR-ATROPHY; CORTICAL DEVELOPMENT; MUTATIONS; MALFORMATIONS;

D O I：

10.1111/epi.18054

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective: DYNC1H1 variants are involved on a disease spectrum from neuromuscular disorders to neurodevelopmental disorders. DYNC1H1-related epilepsy has been reported in small cohorts. We dissect the electroclinical features of 34 patients harboring de novo DYNC1H1 pathogenic variants, identify subphenotypes on the DYNC1H1-related epilepsy spectrum, and compare the genotype-phenotype correlations observed in our cohort with the literature. Methods: Patients harboring de novo DYNC1H1 pathogenic variants were recruited through international collaborations. Clinical data were retrospectively collected. Latent class analysis was performed to identify subphenotypes. Multivariable binary logistic regression analysis was applied to investigate the association with DYNC1H1 protein domains. Results: DYNC1H1-related epilepsy presented with infantile epileptic spasms syndrome (IESS) in 17 subjects (50%), and in 25% of these individuals the epileptic phenotype evolved into Lennox-Gastaut syndrome (LGS). In 12 patients (35%), focal onset epilepsy was defined. In two patients, the epileptic phenotype consisted of generalized myoclonic epilepsy, with a progressive phenotype in one individual harboring a frameshift variant. In approximately 60% of our cohort, seizures were drug-resistant. Malformations of cortical development were noticed in 79% of our patients, mostly on the lissencephaly-pachygyria spectrum, particularly with posterior predominance in a half of them. Midline and infratentorial abnormalities were additionally reported in 45% and 27% of subjects. We have identified three main classes of subphenotypes on the DYNC1H1-related epilepsy spectrum. Significance: We propose a classification in which pathogenic de novo DYNC1H1 variants feature drug-resistant IESS in half of cases with potential evolution to LGS (Class 1), developmental and epileptic encephalopathy other than IESS and LGS (Class 2), or less severe focal or genetic generalized epilepsy including a progressive phenotype (Class 3). We observed an association between stalk domain variants and Class 1 phenotypes. The variants p.Arg309His and p.Arg1962His were common and associated with Class 1 subphenotype in our cohort. These findings may aid genetic counseling of patients with DYNC1H1-related epilepsy.

引用

页码：2728 / 2750

页数：23

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