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. 2024 Sep;65(9):2728-2750.
doi: 10.1111/epi.18054. Epub 2024 Jul 2.

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

Claudia Cuccurullo  1   2 , Emanuele Cerulli Irelli  3 , Lorenzo Ugga  4 , Antonella Riva  5   6 , Alessandra D'Amico  7 , Sara Cabet  8 , Gaetan Lesca  9   10 , Leonilda Bilo  1 , Federico Zara  5   6 , Catrinel Iliescu  11 , Diana Barca  12 , France Fung  13 , Katherine Helbig  13 , Xilma Ortiz-Gonzalez  13 , Helenius J Schelhaas  14 , Marjolein H Willemsen  15 , Inge van der Linden  14 , Laura Canafoglia  16 , Carolina Courage  17   18 , Samuele Gommaraschi  18 , Pedro Gonzalez-Alegre  19 , Tanya Bardakjian  19 , Steffen Syrbe  20 , Elisabeth Schuler  20 , Johannes R Lemke  21 , Stella Vari  22 , Gitte Roende  23 , Mads Bak  24 , Mahbulul Huq  25 , Zoe Powis  26 , Katrine M Johannesen  27 , Trine Bjørg Hammer  27 , Rikke S Møller  27 , Rachel Rabin  28 , John Pappas  28 , Mary L Zupanc  29 , Neda Zadeh  30 , Julie Cohen  31 , Sakkubai Naidu  32 , Ilona Krey  33 , Russell Saneto  34   35 , Jenny Thies  36 , Laura Licchetta  37 , Paolo Tinuper  37 , Francesca Bisulli  37 , Raffaella Minardi  38 , Allan Bayat  27   39 , Nathalie Villeneuve  40 , Florence Molinari  41 , Hormos Salimi Dafsari  42   43   44   45   46   47 , Birk Moller  42   43 , Marie Le Roux  48 , Clara Houdayer  49 , Marilena Vecchi  50 , Isabella Mammi  51 , Elena Fiorini  52   53 , Jacopo Proietti  52   53 , Sofia Ferri  52 , Gaetano Cantalupo  52   53   54 , Domenica Immacolata Battaglia  55   56 , Maria Luigia Gambardella  55 , Ilaria Contaldo  55 , Claudia Brogna  55   57 , Marina Trivisano  58 , Angela De Dominicis  59 , Stefania Maria Bova  59 , Elena Gardella  27 , Pasquale Striano  5   22 , Antonietta Coppola  1
Affiliations

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

Claudia Cuccurullo et al. Epilepsia. 2024 Sep.

Abstract

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.

Keywords: DYNC1H1‐related epilepsy; MCDs; dynein; infantile epileptic spasms syndrome; lissencephaly/pachygyria.

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References

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